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Gwak J, Kim Y, Park SJ, Han J, Jeong KJ, Nguyen MC, Nguyen HQ, Kang H, Goddati M, Kim S, Wu J, Chen H, Choi BY, Lee J. Electron Perturbation for Chiral DNA Point Mutation. ACS NANO 2025; 19:14680-14692. [PMID: 40213973 DOI: 10.1021/acsnano.4c13148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/23/2025]
Abstract
Advances in molecular nanotechnology have enabled the design of systems that exploit nanoscale interactions for enhanced biosensing and diagnostics. Here, we present a plasmonic nematic film (PNF) that leverages nanoscale plasmonic hotspots to amplify electron perturbations induced by DNA mutations. Sequence-specific mismatches, particularly point mutations, significantly alter the local electromagnetic environment, leading to distinct and quantifiable spectral shifts in circular dichroism (CD), denoted as Δλdip. These shifts exhibit a strong correlation with target DNA concentration (R2 > 0.99), enabling precise, quantitative detection of mutation-induced asymmetry. The underlying mechanism is modeled by the asymmetric chiral signal Iasy = ∫ΨPNF*(Ω)ΨPNF dV, where ΨPNF is the wave function of the PNF and Ω represents its chiroptical response. Simulations and electric field analysis further validate that mutation-driven perturbations at the PNF-DNA interface enhance local field intensity at λdip, while no significant changes occur at nonresonant wavelengths. Through this mechanism, the PNF platform achieves over 240% enhancement in chiroptical signal compared to wild-type DNA and enables mutation detection down to 1534 pg. These findings highlight the system's potential for high-specificity diagnostics of clinically relevant mutations, including those associated with hereditary hearing impairment, and may inform the development of future chiral biosensing platforms.
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Affiliation(s)
- Juyong Gwak
- Department of Chemistry, Department of Chemical Engineering and Applied Chemistry, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Yehree Kim
- Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
| | - Se Jeong Park
- Department of Chemistry, Department of Chemical Engineering and Applied Chemistry, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Jinhee Han
- Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
| | - Ki-Jae Jeong
- Research Institute of Materials Chemistry, Chungnam National University, Daejeon 34134, Republic of Korea
| | - My-Chi Nguyen
- Department of Chemistry, Department of Chemical Engineering and Applied Chemistry, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Huu-Quang Nguyen
- Department of Chemistry, Department of Chemical Engineering and Applied Chemistry, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Hyojin Kang
- Department of Chemistry, Department of Chemical Engineering and Applied Chemistry, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Mahendra Goddati
- Department of Chemistry, Department of Chemical Engineering and Applied Chemistry, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Sungwan Kim
- Center for Self-assembly and Complexity, Institute for Basic Science, Pohang 37673, Republic of Korea
| | - Jingyao Wu
- Center for Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai 200444, PR China
| | - Hongxia Chen
- Center for Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai 200444, PR China
| | - Byung Yoon Choi
- Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
| | - Jaebeom Lee
- Department of Chemistry, Department of Chemical Engineering and Applied Chemistry, Chungnam National University, Daejeon 34134, Republic of Korea
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Wang J, Lin Y, Zhuang X, Zhao D, Li B, Zhao Y, Xu Z, Liu F, Dai T, Li W, Jiang M, Yan C, Zhao Y, Ji K. Genotype-Phenotype Correlation in Progressive External Ophthalmoplegia: Insights From a Retrospective Analysis. Neuropathol Appl Neurobiol 2025; 51:e70001. [PMID: 39822040 DOI: 10.1111/nan.70001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 12/31/2024] [Accepted: 01/06/2025] [Indexed: 01/19/2025]
Abstract
BACKGROUND Progressive external ophthalmoplegia (PEO) is a classic manifestation of mitochondrial disease. However, the link between its genetic characteristics and clinical presentations remains poorly investigated. METHODS We analysed the clinical, pathological and genetic characteristics of a large cohort of patients with PEO, based on the type of their mtDNA variations. Eighty-two PEO patients were enrolled and grouped into three categories: mtDNA single large-scale deletions (SLDs), multiple deletions (MulDs) and the m.3243A > G point variant. Patients in the SLD category were further divided into 'common deletion' and 'noncommon deletion' groups based on the presence or absence of a 4977-bp deletion. The mutational load of deleted mtDNA of these patients was comprehensively detected by real-time polymerase chain reaction (RT-PCR). RESULTS SLD Patients showed the highest proportion of cytochrome C oxidase-negative (COX-n) fibres on muscle biopsy. The mutational load of deleted mtDNA exhibited an inverse relationship with deletion length and a direct relationship with the COX-n fibre ratio. Compared with patients having noncommon deletions, those with common deletions tend to have other muscle involvement, lower body mass index (BMI) scores (17 ± 3 vs. 22 ± 4 kg/m2), higher mutational load in muscle (63% ± 22% vs. 46% ± 24%), more COX-n fibres (26% vs. 9%, interquartile range [IQR]: 15%-32% vs. 6%-26%) and higher growth and differentiation factor 15 (GDF15) levels (2583 vs. 1472, IQR: 1746-4081 vs. 924-2155 pg/mL). MulDs patients displayed milder symptoms, especially compared to patients with m.3243A > G variant, as indicated by their later age of onset (31 vs. 13, IQR: 27-49 vs. 6-29 years), higher BMI scores (24.0 ± 4 vs. 16.5 ± 3.4 kg/m2), lower lactate (1.6 ± 1.1 vs. 6.3 ± 6.0 mmol/L) levels and lower proportion of ragged-blue fibres (RBFs) (3 vs. 16, IQR: 1%-9% vs. 7%-27%). CONCLUSION The m.3243A > G variant group exhibits more severe symptoms compared to other subgroups, particularly MulDs patients. In the SLD group, those with common deletions experience more severe clinical and pathological manifestations. These findings enhance our understanding of PEO, facilitating its diagnosis, prognosis and genetic counselling.
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Affiliation(s)
- Jiayin Wang
- Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yan Lin
- Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Xingyu Zhuang
- Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Dandan Zhao
- Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Busu Li
- Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Ying Zhao
- Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Zhe Xu
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
| | - Fuchen Liu
- Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Tingjun Dai
- Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Wei Li
- Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Min Jiang
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
| | - Chuanzhu Yan
- Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingdao, Shandong, China
| | - Yuying Zhao
- Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Kunqian Ji
- Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Shandong Key Laboratory: Magnetic Field-free Medicine & Functional Imaging, Shandong University, Jinan, Shandong, China
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Bulduk BK, Tortajada J, Torres‐Egurrola L, Valiente‐Pallejà A, Martínez‐Leal R, Vilella E, Torrell H, Muntané G, Martorell L. High frequency of mitochondrial DNA rearrangements in the peripheral blood of adults with intellectual disability. JOURNAL OF INTELLECTUAL DISABILITY RESEARCH : JIDR 2025; 69:137-152. [PMID: 39506491 PMCID: PMC11735882 DOI: 10.1111/jir.13197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 10/10/2024] [Accepted: 10/15/2024] [Indexed: 11/08/2024]
Abstract
BACKGROUND Mitochondrial DNA (mtDNA) rearrangements are recognised factors in mitochondrial disorders and ageing, but their involvement in neurodevelopmental disorders, particularly intellectual disability (ID) and autism spectrum disorder (ASD), remains poorly understood. Previous studies have reported mitochondrial dysfunction in individuals with both ID and ASD. The aim of this study was to investigate the prevalence of large-scale mtDNA rearrangements in ID and ID with comorbid ASD (ID-ASD). METHOD We used mtDNA-targeted next-generation sequencing and the MitoSAlt high-throughput computational pipeline in peripheral blood samples from 76 patients with ID (mean age 52.5 years, 37% female), 59 patients with ID-ASD (mean age 41.3 years, 46% female) and 32 healthy controls (mean age 42.4 years, 47% female) from Catalonia. RESULTS The study revealed a high frequency of mtDNA rearrangements in patients with ID, with 10/76 (13.2%) affected individuals. However, the prevalence was significantly lower in patients with ID-ASD 1/59 (1.7%) and in HC 1/32 (3.1%). Among the mtDNA rearrangements, six were identified as deletions (median size 6937 bp and median heteroplasmy level 2.3%) and six as duplications (median size 10 455 bp and median heteroplasmy level 1.9%). One of the duplications, MT-ATP6 m.8765-8793dup (29 bp), was present in four individuals with ID with a median heteroplasmy level of 3.9%. CONCLUSIONS Our results show that mtDNA rearrangements are frequent in patients with ID, but not in those with ID-ASD, when compared to HC. Additionally, MitoSAlt has demonstrated high sensitivity and accuracy in detecting mtDNA rearrangements, even at very low heteroplasmy levels in blood samples. While the high frequency of mtDNA rearrangements in ID is noteworthy, the role of these rearrangements is currently unclear and needs to be confirmed with further data, particularly in post-mitotic tissues and through age-matched control studies.
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Affiliation(s)
- B. K. Bulduk
- Àrea de RecercaHospital Universitari Institut Pere Mata (HUIPM)ReusCataloniaSpain
- Institut d'Investigació Sanitària Pere Virgili (IISPV‐CERCA)Universitat Rovira i Virgili (URV)ReusCataloniaSpain
| | - J. Tortajada
- Àrea de RecercaHospital Universitari Institut Pere Mata (HUIPM)ReusCataloniaSpain
- Institut d'Investigació Sanitària Pere Virgili (IISPV‐CERCA)Universitat Rovira i Virgili (URV)ReusCataloniaSpain
| | - L. Torres‐Egurrola
- Àrea de RecercaHospital Universitari Institut Pere Mata (HUIPM)ReusCataloniaSpain
- Institut d'Investigació Sanitària Pere Virgili (IISPV‐CERCA)Universitat Rovira i Virgili (URV)ReusCataloniaSpain
| | - A. Valiente‐Pallejà
- Àrea de RecercaHospital Universitari Institut Pere Mata (HUIPM)ReusCataloniaSpain
- Institut d'Investigació Sanitària Pere Virgili (IISPV‐CERCA)Universitat Rovira i Virgili (URV)ReusCataloniaSpain
- CIBER de Salud Mental (CIBERSAM)Instituto de Salud Carlos IIIMadridSpain
| | - R. Martínez‐Leal
- Institut d'Investigació Sanitària Pere Virgili (IISPV‐CERCA)Universitat Rovira i Virgili (URV)ReusCataloniaSpain
- CIBER de Salud Mental (CIBERSAM)Instituto de Salud Carlos IIIMadridSpain
- Genètica i Ambient en PsiquiatriaIntellectual Disability and Developmental Disorders Research Unit (UNIVIDD), Fundació VillablancaReusCataloniaSpain
| | - E. Vilella
- Àrea de RecercaHospital Universitari Institut Pere Mata (HUIPM)ReusCataloniaSpain
- Institut d'Investigació Sanitària Pere Virgili (IISPV‐CERCA)Universitat Rovira i Virgili (URV)ReusCataloniaSpain
- CIBER de Salud Mental (CIBERSAM)Instituto de Salud Carlos IIIMadridSpain
| | - H. Torrell
- Centre for Omic Sciences (COS)Joint Unit Universitat Rovira i Virgili‐EURECAT Technology Centre of Catalonia, Unique Scientific and Technical InfrastructuresReusCataloniaSpain
| | - G. Muntané
- Àrea de RecercaHospital Universitari Institut Pere Mata (HUIPM)ReusCataloniaSpain
- Institut d'Investigació Sanitària Pere Virgili (IISPV‐CERCA)Universitat Rovira i Virgili (URV)ReusCataloniaSpain
- CIBER de Salud Mental (CIBERSAM)Instituto de Salud Carlos IIIMadridSpain
- Institut de Biologia Evolutiva (UPF‐CSIC), Department of Medicine and Life SciencesUniversitat Pompeu Fabra, Parc de Recerca Biomèdica de BarcelonaBarcelonaCataloniaSpain
| | - L. Martorell
- Àrea de RecercaHospital Universitari Institut Pere Mata (HUIPM)ReusCataloniaSpain
- Institut d'Investigació Sanitària Pere Virgili (IISPV‐CERCA)Universitat Rovira i Virgili (URV)ReusCataloniaSpain
- CIBER de Salud Mental (CIBERSAM)Instituto de Salud Carlos IIIMadridSpain
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Bej E, Cesare P, d’Angelo M, Volpe AR, Castelli V. Neuronal Cell Rearrangement During Aging: Antioxidant Compounds as a Potential Therapeutic Approach. Cells 2024; 13:1945. [PMID: 39682694 PMCID: PMC11639796 DOI: 10.3390/cells13231945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/02/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
Aging is a natural process that leads to time-related changes and a decrease in cognitive abilities, executive functions, and attention. In neuronal aging, brain cells struggle to respond to oxidative stress. The structure, function, and survival of neurons can be mediated by different pathways that are sensitive to oxidative stress and age-related low-energy states. Mitochondrial impairment is one of the most noticeable signs of brain aging. Damaged mitochondria are thought to be one of the main causes that feed the inflammation related to aging. Also, protein turnover is involved in age-related impairments. The brain, due to its high oxygen usage, is particularly susceptible to oxidative damage. This review explores the mechanisms underlying neuronal cell rearrangement during aging, focusing on morphological changes that contribute to cognitive decline and increased susceptibility to neurodegenerative diseases. Potential therapeutic approaches are discussed, including the use of antioxidants (e.g., Vitamin C, Vitamin E, glutathione, carotenoids, quercetin, resveratrol, and curcumin) to mitigate oxidative damage, enhance mitochondrial function, and maintain protein homeostasis. This comprehensive overview aims to provide insights into the cellular and molecular processes of neuronal aging and highlight promising therapeutic avenues to counteract age-related neuronal deterioration.
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Affiliation(s)
- Erjola Bej
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (E.B.); (P.C.); (M.d.)
- Department of the Chemical-Toxicological and Pharmacological Evaluation of Drugs, Faculty of Pharmacy, Catholic University Our Lady of Good Counsel, 1001 Tirana, Albania
| | - Patrizia Cesare
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (E.B.); (P.C.); (M.d.)
| | - Michele d’Angelo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (E.B.); (P.C.); (M.d.)
| | - Anna Rita Volpe
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (E.B.); (P.C.); (M.d.)
| | - Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (E.B.); (P.C.); (M.d.)
- Department of the Chemical-Toxicological and Pharmacological Evaluation of Drugs, Faculty of Pharmacy, Catholic University Our Lady of Good Counsel, 1001 Tirana, Albania
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Bernardino Gomes TM, Vincent AE, Menger KE, Stewart JB, Nicholls TJ. Mechanisms and pathologies of human mitochondrial DNA replication and deletion formation. Biochem J 2024; 481:683-715. [PMID: 38804971 PMCID: PMC11346376 DOI: 10.1042/bcj20230262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 05/13/2024] [Accepted: 05/14/2024] [Indexed: 05/29/2024]
Abstract
Human mitochondria possess a multi-copy circular genome, mitochondrial DNA (mtDNA), that is essential for cellular energy metabolism. The number of copies of mtDNA per cell, and their integrity, are maintained by nuclear-encoded mtDNA replication and repair machineries. Aberrant mtDNA replication and mtDNA breakage are believed to cause deletions within mtDNA. The genomic location and breakpoint sequences of these deletions show similar patterns across various inherited and acquired diseases, and are also observed during normal ageing, suggesting a common mechanism of deletion formation. However, an ongoing debate over the mechanism by which mtDNA replicates has made it difficult to develop clear and testable models for how mtDNA rearrangements arise and propagate at a molecular and cellular level. These deletions may impair energy metabolism if present in a high proportion of the mtDNA copies within the cell, and can be seen in primary mitochondrial diseases, either in sporadic cases or caused by autosomal variants in nuclear-encoded mtDNA maintenance genes. These mitochondrial diseases have diverse genetic causes and multiple modes of inheritance, and show notoriously broad clinical heterogeneity with complex tissue specificities, which further makes establishing genotype-phenotype relationships challenging. In this review, we aim to cover our current understanding of how the human mitochondrial genome is replicated, the mechanisms by which mtDNA replication and repair can lead to mtDNA instability in the form of large-scale rearrangements, how rearranged mtDNAs subsequently accumulate within cells, and the pathological consequences when this occurs.
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Affiliation(s)
- Tiago M. Bernardino Gomes
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K
- NHS England Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE2 4HH, U.K
| | - Amy E. Vincent
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K
| | - Katja E. Menger
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K
| | - James B. Stewart
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K
| | - Thomas J. Nicholls
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K
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Burr SP, Chinnery PF. Origins of tissue and cell-type specificity in mitochondrial DNA (mtDNA) disease. Hum Mol Genet 2024; 33:R3-R11. [PMID: 38779777 PMCID: PMC11112380 DOI: 10.1093/hmg/ddae059] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 12/21/2023] [Accepted: 02/05/2024] [Indexed: 05/25/2024] Open
Abstract
Mutations of mitochondrial (mt)DNA are a major cause of morbidity and mortality in humans, accounting for approximately two thirds of diagnosed mitochondrial disease. However, despite significant advances in technology since the discovery of the first disease-causing mtDNA mutations in 1988, the comprehensive diagnosis and treatment of mtDNA disease remains challenging. This is partly due to the highly variable clinical presentation linked to tissue-specific vulnerability that determines which organs are affected. Organ involvement can vary between different mtDNA mutations, and also between patients carrying the same disease-causing variant. The clinical features frequently overlap with other non-mitochondrial diseases, both rare and common, adding to the diagnostic challenge. Building on previous findings, recent technological advances have cast further light on the mechanisms which underpin the organ vulnerability in mtDNA diseases, but our understanding is far from complete. In this review we explore the origins, current knowledge, and future directions of research in this area.
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Affiliation(s)
- Stephen P Burr
- Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, United Kingdom
| | - Patrick F Chinnery
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, United Kingdom
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Tan DX. Mitochondrial dysfunction, a weakest link of network of aging, relation to innate intramitochondrial immunity of DNA recognition receptors. Mitochondrion 2024; 76:101886. [PMID: 38663836 DOI: 10.1016/j.mito.2024.101886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 04/21/2024] [Accepted: 04/22/2024] [Indexed: 04/30/2024]
Abstract
Aging probably is the most complexed process in biology. It is manifested by a variety of hallmarks. These hallmarks weave a network of aging; however, each hallmark is not uniformly strong for the network. It is the weakest link determining the strengthening of the network of aging, or the maximum lifespan of an organism. Therefore, only improvement of the weakest link has the chance to increase the maximum lifespan but not others. We hypothesize that mitochondrial dysfunction is the weakest link of the network of aging. It may origin from the innate intramitochondrial immunity related to the activities of pathogen DNA recognition receptors. These receptors recognize mtDNA as the PAMP or DAMP to initiate the immune or inflammatory reactions. Evidence has shown that several of these receptors including TLR9, cGAS and IFI16 can be translocated into mitochondria. The potentially intramitochondrial presented pathogen DNA recognition receptors have the capacity to attack the exposed second structures of the mtDNA during its transcriptional or especially the replicational processes, leading to the mtDNA mutation, deletion, heteroplasmy colonization, mitochondrial dysfunction, and alterations of other hallmarks, as well as aging. Pre-consumption of the intramitochondrial presented pathogen DNA recognition receptors by medical interventions including development of mitochondrial targeted small molecule which can neutralize these receptors may retard or even reverse the aging to significantly improve the maximum lifespan of the organisms.
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Affiliation(s)
- Dun-Xian Tan
- Department of Cell Systems and Anatomy, UT Health San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
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Fragkoulis G, Hangas A, Fekete Z, Michell C, Moraes C, Willcox S, Griffith JD, Goffart S, Pohjoismäki JO. Linear DNA-driven recombination in mammalian mitochondria. Nucleic Acids Res 2024; 52:3088-3105. [PMID: 38300793 PMCID: PMC11014290 DOI: 10.1093/nar/gkae040] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 01/11/2024] [Indexed: 02/03/2024] Open
Abstract
Mitochondrial DNA (mtDNA) recombination in animals has remained enigmatic due to its uniparental inheritance and subsequent homoplasmic state, which excludes the biological need for genetic recombination, as well as limits tools to study it. However, molecular recombination is an important genome maintenance mechanism for all organisms, most notably being required for double-strand break repair. To demonstrate the existence of mtDNA recombination, we took advantage of a cell model with two different types of mitochondrial genomes and impaired its ability to degrade broken mtDNA. The resulting excess of linear DNA fragments caused increased formation of cruciform mtDNA, appearance of heterodimeric mtDNA complexes and recombinant mtDNA genomes, detectable by Southern blot and by long range PacBio® HiFi sequencing approach. Besides utilizing different electrophoretic methods, we also directly observed molecular complexes between different mtDNA haplotypes and recombination intermediates using transmission electron microscopy. We propose that the known copy-choice recombination by mitochondrial replisome could be sufficient for the needs of the small genome, thus removing the requirement for a specialized mitochondrial recombinase. The error-proneness of this system is likely to contribute to the formation of pathological mtDNA rearrangements.
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Affiliation(s)
- Georgios Fragkoulis
- Department of Environmental and Biological Sciences, University of Eastern Finland, PO Box 111, 80101 Joensuu, Finland
| | - Anu Hangas
- Department of Environmental and Biological Sciences, University of Eastern Finland, PO Box 111, 80101 Joensuu, Finland
| | - Zsófia Fekete
- Department of Environmental and Biological Sciences, University of Eastern Finland, PO Box 111, 80101 Joensuu, Finland
- Department of Genetics and Genomics, Institute of Genetics and Biotechnology, Hungarian University of Agriculture and Life Sciences, Gödöllő, Hungary
- Doctoral School of Animal Biotechnology and Animal Science, Hungarian University of Agriculture and Life Sciences, Gödöllő, Hungary
| | - Craig Michell
- Red Sea Research Center, Division of Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Carlos T Moraes
- Department of Neurology, University of Miami Miller School of Medicine, Miami,FL, USA
| | - Smaranda Willcox
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, USA
| | - Jack D Griffith
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, USA
| | - Steffi Goffart
- Department of Environmental and Biological Sciences, University of Eastern Finland, PO Box 111, 80101 Joensuu, Finland
| | - Jaakko L O Pohjoismäki
- Department of Environmental and Biological Sciences, University of Eastern Finland, PO Box 111, 80101 Joensuu, Finland
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Hong S, Kim S, Kim K, Lee H. Clinical Approaches for Mitochondrial Diseases. Cells 2023; 12:2494. [PMID: 37887337 PMCID: PMC10605124 DOI: 10.3390/cells12202494] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/18/2023] [Accepted: 10/19/2023] [Indexed: 10/28/2023] Open
Abstract
Mitochondria are subcontractors dedicated to energy production within cells. In human mitochondria, almost all mitochondrial proteins originate from the nucleus, except for 13 subunit proteins that make up the crucial system required to perform 'oxidative phosphorylation (OX PHOS)', which are expressed by the mitochondria's self-contained DNA. Mitochondrial DNA (mtDNA) also encodes 2 rRNA and 22 tRNA species. Mitochondrial DNA replicates almost autonomously, independent of the nucleus, and its heredity follows a non-Mendelian pattern, exclusively passing from mother to children. Numerous studies have identified mtDNA mutation-related genetic diseases. The consequences of various types of mtDNA mutations, including insertions, deletions, and single base-pair mutations, are studied to reveal their relationship to mitochondrial diseases. Most mitochondrial diseases exhibit fatal symptoms, leading to ongoing therapeutic research with diverse approaches such as stimulating the defective OXPHOS system, mitochondrial replacement, and allotropic expression of defective enzymes. This review provides detailed information on two topics: (1) mitochondrial diseases caused by mtDNA mutations, and (2) the mechanisms of current treatments for mitochondrial diseases and clinical trials.
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Affiliation(s)
- Seongho Hong
- Korea Mouse Phenotyping Center, Seoul National University, Seoul 08826, Republic of Korea;
- Department of Medicine, Korea University College of Medicine, Seoul 02708, Republic of Korea
| | - Sanghun Kim
- Laboratory Animal Resource and Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea;
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Kyoungmi Kim
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea
- Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Hyunji Lee
- Department of Medicine, Korea University College of Medicine, Seoul 02708, Republic of Korea
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10
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Doimo M, Chaudhari N, Abrahamsson S, L’Hôte V, Nguyen TH, Berner A, Ndi M, Abrahamsson A, Das R, Aasumets K, Goffart S, Pohjoismäki JLO, López MD, Chorell E, Wanrooij S. Enhanced mitochondrial G-quadruplex formation impedes replication fork progression leading to mtDNA loss in human cells. Nucleic Acids Res 2023; 51:7392-7408. [PMID: 37351621 PMCID: PMC10415151 DOI: 10.1093/nar/gkad535] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 06/09/2023] [Indexed: 06/24/2023] Open
Abstract
Mitochondrial DNA (mtDNA) replication stalling is considered an initial step in the formation of mtDNA deletions that associate with genetic inherited disorders and aging. However, the molecular details of how stalled replication forks lead to mtDNA deletions accumulation are still unclear. Mitochondrial DNA deletion breakpoints preferentially occur at sequence motifs predicted to form G-quadruplexes (G4s), four-stranded nucleic acid structures that can fold in guanine-rich regions. Whether mtDNA G4s form in vivo and their potential implication for mtDNA instability is still under debate. In here, we developed new tools to map G4s in the mtDNA of living cells. We engineered a G4-binding protein targeted to the mitochondrial matrix of a human cell line and established the mtG4-ChIP method, enabling the determination of mtDNA G4s under different cellular conditions. Our results are indicative of transient mtDNA G4 formation in human cells. We demonstrate that mtDNA-specific replication stalling increases formation of G4s, particularly in the major arc. Moreover, elevated levels of G4 block the progression of the mtDNA replication fork and cause mtDNA loss. We conclude that stalling of the mtDNA replisome enhances mtDNA G4 occurrence, and that G4s not resolved in a timely manner can have a negative impact on mtDNA integrity.
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Affiliation(s)
- Mara Doimo
- Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
- Department of Women and Children Health, University of Padova, 35128 Padova, Italy
| | - Namrata Chaudhari
- Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
| | - Sanna Abrahamsson
- Bioinformatics and Data Centre, Sahlgrenska Academy, University of Gothenburg, 41390 Gothenburg, Sweden
| | - Valentin L’Hôte
- Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
| | - Tran V H Nguyen
- Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
| | - Andreas Berner
- Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
| | - Mama Ndi
- Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
| | | | | | - Koit Aasumets
- Department of Environmental and Biological Sciences, University of Eastern Finland, FI-80101 Joensuu, Finland
| | - Steffi Goffart
- Department of Environmental and Biological Sciences, University of Eastern Finland, FI-80101 Joensuu, Finland
| | - Jaakko L O Pohjoismäki
- Department of Environmental and Biological Sciences, University of Eastern Finland, FI-80101 Joensuu, Finland
| | - Marcela Dávila López
- Bioinformatics and Data Centre, Sahlgrenska Academy, University of Gothenburg, 41390 Gothenburg, Sweden
| | - Erik Chorell
- Department of Chemistry, Umeå University, 90187 Umeå, Sweden
| | - Sjoerd Wanrooij
- Department of Medical Biochemistry and Biophysics, Umeå University, 90187 Umeå, Sweden
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11
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Lareau CA, Dubois SM, Buquicchio FA, Hsieh YH, Garg K, Kautz P, Nitsch L, Praktiknjo SD, Maschmeyer P, Verboon JM, Gutierrez JC, Yin Y, Fiskin E, Luo W, Mimitou EP, Muus C, Malhotra R, Parikh S, Fleming MD, Oevermann L, Schulte J, Eckert C, Kundaje A, Smibert P, Vardhana SA, Satpathy AT, Regev A, Sankaran VG, Agarwal S, Ludwig LS. Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells. Nat Genet 2023; 55:1198-1209. [PMID: 37386249 PMCID: PMC10548551 DOI: 10.1038/s41588-023-01433-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 05/24/2023] [Indexed: 07/01/2023]
Abstract
Pathogenic mutations in mitochondrial DNA (mtDNA) compromise cellular metabolism, contributing to cellular heterogeneity and disease. Diverse mutations are associated with diverse clinical phenotypes, suggesting distinct organ- and cell-type-specific metabolic vulnerabilities. Here we establish a multi-omics approach to quantify deletions in mtDNA alongside cell state features in single cells derived from six patients across the phenotypic spectrum of single large-scale mtDNA deletions (SLSMDs). By profiling 206,663 cells, we reveal the dynamics of pathogenic mtDNA deletion heteroplasmy consistent with purifying selection and distinct metabolic vulnerabilities across T-cell states in vivo and validate these observations in vitro. By extending analyses to hematopoietic and erythroid progenitors, we reveal mtDNA dynamics and cell-type-specific gene regulatory adaptations, demonstrating the context-dependence of perturbing mitochondrial genomic integrity. Collectively, we report pathogenic mtDNA heteroplasmy dynamics of individual blood and immune cells across lineages, demonstrating the power of single-cell multi-omics for revealing fundamental properties of mitochondrial genetics.
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Affiliation(s)
- Caleb A Lareau
- Department of Pathology, Stanford University, Stanford, CA, USA.
- Parker Institute of Cancer Immunotherapy, San Francisco, CA, USA.
- Department of Genetics, Stanford University, Stanford, CA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
| | - Sonia M Dubois
- Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | | | - Yu-Hsin Hsieh
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
| | - Kopal Garg
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Pauline Kautz
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
- Technische Universität Berlin, Institute of Biotechnology, Berlin, Germany
| | - Lena Nitsch
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
- Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Berlin, Germany
| | - Samantha D Praktiknjo
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Patrick Maschmeyer
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Jeffrey M Verboon
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | | | - Yajie Yin
- Department of Pathology, Stanford University, Stanford, CA, USA
| | | | - Wendy Luo
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Eleni P Mimitou
- Technology Innovation Lab, New York Genome Center, New York City, NY, USA
- Immunai, New York City, NY, USA
| | - Christoph Muus
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA
| | - Rhea Malhotra
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Sumit Parikh
- Center for Pediatric Neurosciences, Mitochondrial Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Mark D Fleming
- Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Lena Oevermann
- Department of Pediatric Oncology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Johannes Schulte
- Department of Pediatric Oncology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Cornelia Eckert
- Department of Pediatric Oncology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Anshul Kundaje
- Department of Genetics, Stanford University, Stanford, CA, USA
- Department of Computer Science, Stanford University, Stanford, CA, USA
| | - Peter Smibert
- Technology Innovation Lab, New York Genome Center, New York City, NY, USA
- 10x Genomics, San Francisco, CA, USA
| | | | - Ansuman T Satpathy
- Department of Pathology, Stanford University, Stanford, CA, USA
- Parker Institute of Cancer Immunotherapy, San Francisco, CA, USA
| | - Aviv Regev
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Biology and Koch Institute, Massachusetts Institute of Technology, Cambridge, MA, USA.
- Genentech, San Francisco, CA, USA.
| | - Vijay G Sankaran
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
| | - Suneet Agarwal
- Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
| | - Leif S Ludwig
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany.
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany.
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12
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Dong LF, Rohlena J, Zobalova R, Nahacka Z, Rodriguez AM, Berridge MV, Neuzil J. Mitochondria on the move: Horizontal mitochondrial transfer in disease and health. J Cell Biol 2023; 222:213873. [PMID: 36795453 PMCID: PMC9960264 DOI: 10.1083/jcb.202211044] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 01/12/2023] [Accepted: 02/01/2023] [Indexed: 02/17/2023] Open
Abstract
Mammalian genes were long thought to be constrained within somatic cells in most cell types. This concept was challenged recently when cellular organelles including mitochondria were shown to move between mammalian cells in culture via cytoplasmic bridges. Recent research in animals indicates transfer of mitochondria in cancer and during lung injury in vivo, with considerable functional consequences. Since these pioneering discoveries, many studies have confirmed horizontal mitochondrial transfer (HMT) in vivo, and its functional characteristics and consequences have been described. Additional support for this phenomenon has come from phylogenetic studies. Apparently, mitochondrial trafficking between cells occurs more frequently than previously thought and contributes to diverse processes including bioenergetic crosstalk and homeostasis, disease treatment and recovery, and development of resistance to cancer therapy. Here we highlight current knowledge of HMT between cells, focusing primarily on in vivo systems, and contend that this process is not only (patho)physiologically relevant, but also can be exploited for the design of novel therapeutic approaches.
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Affiliation(s)
- Lan-Feng Dong
- https://ror.org/02sc3r913School of Pharmacy and Medical Sciences, Griffith University, Southport, Australia,Lan-Feng Dong:
| | - Jakub Rohlena
- https://ror.org/00wzqmx94Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague-West, Czech Republic
| | - Renata Zobalova
- https://ror.org/00wzqmx94Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague-West, Czech Republic
| | - Zuzana Nahacka
- https://ror.org/00wzqmx94Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague-West, Czech Republic
| | | | | | - Jiri Neuzil
- https://ror.org/02sc3r913School of Pharmacy and Medical Sciences, Griffith University, Southport, Australia,https://ror.org/00wzqmx94Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague-West, Czech Republic,Faculty of Science, Charles University, Prague, Czech Republic,First Faculty of Medicine, Charles University, Prague, Czech Republic,Correspondence to Jiri Neuzil: ,
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13
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White K, Someya S. The roles of NADPH and isocitrate dehydrogenase in cochlear mitochondrial antioxidant defense and aging. Hear Res 2023; 427:108659. [PMID: 36493529 PMCID: PMC11446251 DOI: 10.1016/j.heares.2022.108659] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 11/04/2022] [Accepted: 11/23/2022] [Indexed: 11/26/2022]
Abstract
Hearing loss is the third most prevalent chronic health condition affecting older adults. Age-related hearing loss affects one in three adults over 65 years of age and is caused by both extrinsic and intrinsic factors, including genetics, aging, and exposure to noise and toxins. All cells possess antioxidant defense systems that play an important role in protecting cells against these factors. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) serves as a co-factor for antioxidant enzymes such as glutathione reductase and thioredoxin reductase and is produced by glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, isocitrate dehydrogenase 1 (IDH1) or malic enzyme 1 in the cytosol, while in the mitochondria, NADPH is generated from mitochondrial transhydrogenase, glutamate dehydrogenase, malic enzyme 3 or IDH2. There are three isoforms of IDH: cytosolic IDH1, and mitochondrial IDH2 and IDH3. Of these, IDH2 is thought to be the major supplier of NADPH to the mitochondrial antioxidant defense system. The NADP+/NADPH and NAD+/NADH couples are essential for maintaining a large array of biological processes, including cellular redox state, and energy metabolism, mitochondrial function. A growing body of evidence indicates that mitochondrial dysfunction contributes to age-related structural or functional changes of cochlear sensory hair cells and neurons, leading to hearing impairments. In this review, we describe the current understanding of the roles of NADPH and IDHs in cochlear mitochondrial antioxidant defense and aging.
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Affiliation(s)
- Karessa White
- Charlie Brigade Support Medical Company, 2/1 ABCT, United States Army, Fort Riley, KS, USA
| | - Shinichi Someya
- Department of Physiology and Aging, University of Florida, Gainesville, Florida, USA.
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14
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Whitehall JC, Smith ALM, Greaves LC. Mitochondrial DNA Mutations and Ageing. Subcell Biochem 2023; 102:77-98. [PMID: 36600130 DOI: 10.1007/978-3-031-21410-3_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Mitochondria are subcellular organelles present in most eukaryotic cells which play a significant role in numerous aspects of cell biology. These include carbohydrate and fatty acid metabolism to generate cellular energy through oxidative phosphorylation, apoptosis, cell signalling, haem biosynthesis and reactive oxygen species production. Mitochondrial dysfunction is a feature of many human ageing tissues, and since the discovery that mitochondrial DNA mutations were a major underlying cause of changes in oxidative phosphorylation capacity, it has been proposed that they have a role in human ageing. However, there is still much debate on whether mitochondrial DNA mutations play a causal role in ageing or are simply a consequence of the ageing process. This chapter describes the structure of mammalian mitochondria, and the unique features of mitochondrial genetics, and reviews the current evidence surrounding the role of mitochondrial DNA mutations in the ageing process. It then focusses on more recent discoveries regarding the role of mitochondrial dysfunction in stem cell ageing and age-related inflammation.
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Affiliation(s)
- Julia C Whitehall
- Wellcome Centre for Mitochondrial Research, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Anna L M Smith
- Wellcome Centre for Mitochondrial Research, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Laura C Greaves
- Wellcome Centre for Mitochondrial Research, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK.
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15
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Schwartz B, Gjini P, Gopal DM, Fetterman JL. Inefficient Batteries in Heart Failure: Metabolic Bottlenecks Disrupting the Mitochondrial Ecosystem. JACC Basic Transl Sci 2022; 7:1161-1179. [PMID: 36687274 PMCID: PMC9849281 DOI: 10.1016/j.jacbts.2022.03.017] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/25/2022] [Accepted: 03/29/2022] [Indexed: 02/01/2023]
Abstract
Mitochondrial abnormalities have long been described in the setting of cardiomyopathies and heart failure (HF), yet the mechanisms of mitochondrial dysfunction in cardiac pathophysiology remain poorly understood. Many studies have described HF as an energy-deprived state characterized by a decline in adenosine triphosphate production, largely driven by impaired oxidative phosphorylation. However, impairments in oxidative phosphorylation extend beyond a simple decline in adenosine triphosphate production and, in fact, reflect pervasive metabolic aberrations that cannot be fully appreciated from the isolated, often siloed, interrogation of individual aspects of mitochondrial function. With the application of broader and deeper examinations into mitochondrial and metabolic systems, recent data suggest that HF with preserved ejection fraction is likely metabolically disparate from HF with reduced ejection fraction. In our review, we introduce the concept of the mitochondrial ecosystem, comprising intricate systems of metabolic pathways and dynamic changes in mitochondrial networks and subcellular locations. The mitochondrial ecosystem exists in a delicate balance, and perturbations in one component often have a ripple effect, influencing both upstream and downstream cellular pathways with effects enhanced by mitochondrial genetic variation. Expanding and deepening our vantage of the mitochondrial ecosystem in HF is critical to identifying consistent metabolic perturbations to develop therapeutics aimed at preventing and improving outcomes in HF.
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Key Words
- ADP, adenosine diphosphate
- ANT1, adenine translocator 1
- ATP, adenosine triphosphate
- CVD, cardiovascular disease
- DCM, dilated cardiomyopathy
- DRP-1, dynamin-related protein 1
- EET, epoxyeicosatrienoic acid
- FADH2/FAD, flavin adenine dinucleotide
- HETE, hydroxyeicosatetraenoic acid
- HF, heart failure
- HFpEF, heart failure with preserved ejection fraction
- HFrEF, heart failure with reduced ejection fraction
- HIF1α, hypoxia-inducible factor 1α
- LV, left ventricle
- LVAD, left ventricular assist device
- LVEF, left ventricular ejection fraction
- NADH/NAD+, nicotinamide adenine dinucleotide
- OPA1, optic atrophy protein 1
- OXPHOS, oxidative phosphorylation
- PGC1-α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha
- SIRT1-7, sirtuins 1-7
- cardiomyopathy
- heart failure
- iPLA2γ, Ca2+-independent mitochondrial phospholipase
- mPTP, mitochondrial permeability transition pore
- metabolism
- mitochondria
- mitochondrial ecosystem
- mtDNA, mitochondrial DNA
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Affiliation(s)
- Brian Schwartz
- Evans Department of Medicine, Section of Internal Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Petro Gjini
- Evans Department of Medicine, Section of Internal Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Deepa M Gopal
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Jessica L Fetterman
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA
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16
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Kong M, Guo L, Xu W, He C, Jia X, Zhao Z, Gu Z. Aging-associated accumulation of mitochondrial DNA mutations in tumor origin. LIFE MEDICINE 2022; 1:149-167. [PMID: 39871923 PMCID: PMC11749795 DOI: 10.1093/lifemedi/lnac014] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/27/2022] [Indexed: 01/29/2025]
Abstract
The majority of cancer patients are among aged population, suggesting an urgent need to advance our knowledge on complicated relationship between aging and cancer. It has been hypothesized that metabolic changes during aging could act as a driver for tumorigenesis. Given the fact that mitochondrial DNA (mtDNA) mutations are common in both tumors and aged tissues, it is interesting to contemplate possible role of age-related mtDNA mutations in tumorigenesis. MtDNA encodes genes essential for mitochondrial metabolism, and mtDNA mutates at a much higher rate than nuclear genome. Random drifting of somatic mtDNA mutations, as a result of cell division or mitochondrial turnover during aging, may lead to more and more cells harboring high-frequency pathogenic mtDNA mutations, albeit at different loci, in single-cells. Such mutations can induce metabolic reprogramming, nuclear genome instability and immune response, which might increase the likelihood of tumorigenesis. In this review, we summarize current understanding of how mtDNA mutations accumulate with aging and how these mutations could mechanistically contribute to tumor origin. We also discuss potential prevention strategies for mtDNA mutation-induced tumorigenesis, and future works needed in this direction.
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Affiliation(s)
- Minghua Kong
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
- School of Life Sciences, Westlake University, Hangzhou 310024, China
| | - Lishu Guo
- Center for Mitochondrial Genetics and Health, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou 511400, China
| | - Weilin Xu
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Chengpeng He
- Center for Mitochondrial Genetics and Health, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou 511400, China
| | - Xiaoyan Jia
- Center for Genomic Technologies, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou 511400, China
| | - Zhiyao Zhao
- Center for Mitochondrial Genetics and Health, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou 511400, China
| | - Zhenglong Gu
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
- Center for Mitochondrial Genetics and Health, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou 511400, China
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17
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Stenberg S, Li J, Gjuvsland AB, Persson K, Demitz-Helin E, González Peña C, Yue JX, Gilchrist C, Ärengård T, Ghiaci P, Larsson-Berglund L, Zackrisson M, Smits S, Hallin J, Höög JL, Molin M, Liti G, Omholt SW, Warringer J. Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation. eLife 2022; 11:e76095. [PMID: 35801695 PMCID: PMC9427111 DOI: 10.7554/elife.76095] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 07/07/2022] [Indexed: 11/15/2022] Open
Abstract
Deletion of mitochondrial DNA in eukaryotes is currently attributed to rare accidental events associated with mitochondrial replication or repair of double-strand breaks. We report the discovery that yeast cells arrest harmful intramitochondrial superoxide production by shutting down respiration through genetically controlled deletion of mitochondrial oxidative phosphorylation genes. We show that this process critically involves the antioxidant enzyme superoxide dismutase 2 and two-way mitochondrial-nuclear communication through Rtg2 and Rtg3. While mitochondrial DNA homeostasis is rapidly restored after cessation of a short-term superoxide stress, long-term stress causes maladaptive persistence of the deletion process, leading to complete annihilation of the cellular pool of intact mitochondrial genomes and irrevocable loss of respiratory ability. This shows that oxidative stress-induced mitochondrial impairment may be under strict regulatory control. If the results extend to human cells, the results may prove to be of etiological as well as therapeutic importance with regard to age-related mitochondrial impairment and disease.
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Affiliation(s)
- Simon Stenberg
- Centre for Integrative Genetics, Department of Animal and Aquacultural Sciences, Norwegian University of Life SciencesÅsNorway
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | - Jing Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterGuangzhouChina
- Université Côte d’Azur, CNRS, INSERM, IRCANNiceFrance
| | - Arne B Gjuvsland
- Centre for Integrative Genetics, Department of Animal and Aquacultural Sciences, Norwegian University of Life SciencesÅsNorway
| | - Karl Persson
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | - Erik Demitz-Helin
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | - Carles González Peña
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | - Jia-Xing Yue
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterGuangzhouChina
- Université Côte d’Azur, CNRS, INSERM, IRCANNiceFrance
| | - Ciaran Gilchrist
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | - Timmy Ärengård
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | - Payam Ghiaci
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | - Lisa Larsson-Berglund
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | - Martin Zackrisson
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | - Silvana Smits
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | - Johan Hallin
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | - Johanna L Höög
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
| | - Mikael Molin
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
- Department of Biology and Biological Engineering, Chalmers University of TechnologyGothenburgSweden
| | - Gianni Liti
- Université Côte d’Azur, CNRS, INSERM, IRCANNiceFrance
| | - Stig W Omholt
- Department of Circulation and Medical Imaging, Cardiac Exercise Research Group, Norwegian University of Science and TechnologyTrondheimNorway
| | - Jonas Warringer
- Department of Chemistry and Molecular Biology, University of GothenburgGothenburgSweden
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18
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Schreier HK, Wiehe RS, Ricchetti M, Wiesmüller L. Polymerase ζ is Involved in Mitochondrial DNA Maintenance Processes in Concert with APE1 Activity. Genes (Basel) 2022; 13:genes13050879. [PMID: 35627264 PMCID: PMC9141751 DOI: 10.3390/genes13050879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 05/10/2022] [Accepted: 05/11/2022] [Indexed: 01/25/2023] Open
Abstract
Mitochondrial DNA (mtDNA) damaged by reactive oxygen species (ROS) triggers so far poorly understood processes of mtDNA maintenance that are coordinated by a complex interplay among DNA repair, DNA degradation, and DNA replication. This study was designed to identify the proteins involved in mtDNA maintenance by applying a special long-range PCR, reflecting mtDNA integrity in the minor arc. A siRNA screening of literature-based candidates was performed under conditions of enforced oxidative phosphorylation revealing the functional group of polymerases and therein polymerase ζ (POLZ) as top hits. Thus, POLZ knockdown caused mtDNA accumulation, which required the activity of the base excision repair (BER) nuclease APE1, and was followed by compensatory mtDNA replication determined by the single-cell mitochondrial in situ hybridization protocol (mTRIP). Quenching reactive oxygen species (ROS) in mitochondria unveiled an additional, ROS-independent involvement of POLZ in the formation of a typical deletion in the minor arc region. Together with data demonstrating the localization of POLZ in mitochondria, we suggest that POLZ plays a significant role in mtDNA turnover, particularly under conditions of oxidative stress.
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Affiliation(s)
- Heike Katrin Schreier
- Department of Obstetrics and Gynecology, Ulm University, 89075 Ulm, Germany; (H.K.S.); (R.S.W.)
| | - Rahel Stefanie Wiehe
- Department of Obstetrics and Gynecology, Ulm University, 89075 Ulm, Germany; (H.K.S.); (R.S.W.)
| | - Miria Ricchetti
- Department of Developmental and Stem Cell Biology, Institute Pasteur, CEDEX 15, 75724 Paris, France;
| | - Lisa Wiesmüller
- Department of Obstetrics and Gynecology, Ulm University, 89075 Ulm, Germany; (H.K.S.); (R.S.W.)
- Correspondence:
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19
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Kumar R, Harilal S, Thomas Parambi DG, Kanthlal S, Rahman MA, Alexiou A, Batiha GES, Mathew B. The Role of Mitochondrial Genes in Neurodegenerative Disorders. Curr Neuropharmacol 2022; 20:824-835. [PMID: 34503413 PMCID: PMC9881096 DOI: 10.2174/1570159x19666210908163839] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 07/09/2021] [Accepted: 09/07/2021] [Indexed: 11/22/2022] Open
Abstract
Mitochondrial disorders are clinically heterogeneous, resulting from nuclear gene and mitochondrial mutations that disturb the mitochondrial functions and dynamics. There is a lack of evidence linking mtDNA mutations to neurodegenerative disorders, mainly due to the absence of noticeable neuropathological lesions in postmortem samples. This review describes various gene mutations in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. These abnormalities, including PINK1, Parkin, and SOD1 mutations, seem to reveal mitochondrial dysfunctions due to either mtDNA mutation or deletion, the mechanism of which remains unclear in depth.
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Affiliation(s)
- Rajesh Kumar
- Department of Pharmacy, Kerala University of Health Sciences, Thrissur, Kerala, India
| | - Seetha Harilal
- Department of Pharmacy, Kerala University of Health Sciences, Thrissur, Kerala, India
| | - Della Grace Thomas Parambi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Al Jouf-2014, Saudi Arabia
| | - S.K. Kanthlal
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi-682 041, India
| | - Md Atiar Rahman
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong, Bangladesh
| | - Athanasios Alexiou
- Novel Global Community Educational Foundation, Hebersham, Australia;,AFNP Med Austria, Wien, Austria
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, AlBeheira, Egypt
| | - Bijo Mathew
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi-682 041, India,Address correspondence to this author at the Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi-682 041, India; E-mails: ;
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20
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OUP accepted manuscript. Hum Reprod 2022; 37:669-679. [DOI: 10.1093/humrep/deac024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 01/11/2022] [Indexed: 11/13/2022] Open
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21
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Moreira JD, Gopal DM, Kotton DN, Fetterman JL. Gaining Insight into Mitochondrial Genetic Variation and Downstream Pathophysiology: What Can i(PSCs) Do? Genes (Basel) 2021; 12:1668. [PMID: 34828274 PMCID: PMC8624338 DOI: 10.3390/genes12111668] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 12/14/2022] Open
Abstract
Mitochondria are specialized organelles involved in energy production that have retained their own genome throughout evolutionary history. The mitochondrial genome (mtDNA) is maternally inherited and requires coordinated regulation with nuclear genes to produce functional enzyme complexes that drive energy production. Each mitochondrion contains 5-10 copies of mtDNA and consequently, each cell has several hundreds to thousands of mtDNAs. Due to the presence of multiple copies of mtDNA in a mitochondrion, mtDNAs with different variants may co-exist, a condition called heteroplasmy. Heteroplasmic variants can be clonally expanded, even in post-mitotic cells, as replication of mtDNA is not tied to the cell-division cycle. Heteroplasmic variants can also segregate during germ cell formation, underlying the inheritance of some mitochondrial mutations. Moreover, the uneven segregation of heteroplasmic variants is thought to underlie the heterogeneity of mitochondrial variation across adult tissues and resultant differences in the clinical presentation of mitochondrial disease. Until recently, however, the mechanisms mediating the relation between mitochondrial genetic variation and disease remained a mystery, largely due to difficulties in modeling human mitochondrial genetic variation and diseases. The advent of induced pluripotent stem cells (iPSCs) and targeted gene editing of the nuclear, and more recently mitochondrial, genomes now provides the ability to dissect how genetic variation in mitochondrial genes alter cellular function across a variety of human tissue types. This review will examine the origins of mitochondrial heteroplasmic variation and propagation, and the tools used to model mitochondrial genetic diseases. Additionally, we discuss how iPSC technologies represent an opportunity to advance our understanding of human mitochondrial genetics in disease.
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Affiliation(s)
- Jesse D. Moreira
- Evans Department of Medicine and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA; (J.D.M.); (D.M.G.)
| | - Deepa M. Gopal
- Evans Department of Medicine and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA; (J.D.M.); (D.M.G.)
- Cardiovascular Medicine Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
| | - Darrell N. Kotton
- Boston Medical Center, Center for Regenerative Medicine of Boston University, Boston, MA 02118, USA;
- The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
| | - Jessica L. Fetterman
- Evans Department of Medicine and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA; (J.D.M.); (D.M.G.)
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22
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Elstner M, Olszewski K, Prokisch H, Klopstock T, Murgia M. Multi-Omics Approach to Mitochondrial DNA Damage in Human Muscle Fibers. Int J Mol Sci 2021; 22:ijms222011080. [PMID: 34681740 PMCID: PMC8537949 DOI: 10.3390/ijms222011080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/05/2021] [Accepted: 10/10/2021] [Indexed: 11/16/2022] Open
Abstract
Mitochondrial DNA deletions affect energy metabolism at tissue-specific and cell-specific threshold levels, but the pathophysiological mechanisms determining cell fate remain poorly understood. Chronic progressive external ophthalmoplegia (CPEO) is caused by mtDNA deletions and characterized by a mosaic distribution of muscle fibers with defective cytochrome oxidase (COX) activity, interspersed among fibers with retained functional respiratory chain. We used diagnostic histochemistry to distinguish COX-negative from COX-positive fibers in nine muscle biopsies from CPEO patients and performed laser capture microdissection (LCM) coupled to genome-wide gene expression analysis. To gain molecular insight into the pathogenesis, we applied network and pathway analysis to highlight molecular differences of the COX-positive and COX-negative fiber transcriptome. We then integrated our results with proteomics data that we previously obtained comparing COX-positive and COX-negative fiber sections from three other patients. By virtue of the combination of LCM and a multi-omics approach, we here provide a comprehensive resource to tackle the pathogenic changes leading to progressive respiratory chain deficiency and disease in mitochondrial deletion syndromes. Our data show that COX-negative fibers upregulate transcripts involved in translational elongation and protein synthesis. Furthermore, based on functional annotation analysis, we find that mitochondrial transcripts are the most enriched among those with significantly different expression between COX-positive and COX-negative fibers, indicating that our unbiased large-scale approach resolves the core of the pathogenic changes. Further enrichments include transcripts encoding LIM domain proteins, ubiquitin ligases, proteins involved in RNA turnover, and, interestingly, cell cycle arrest and cell death. These pathways may thus have a functional association to the molecular pathogenesis of the disease. Overall, the transcriptome and proteome show a low degree of correlation in CPEO patients, suggesting a relevant contribution of post-transcriptional mechanisms in shaping this disease phenotype.
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Affiliation(s)
- Matthias Elstner
- Department of Neurology, Technical University Munich, 81675 Munich, Germany;
| | - Konrad Olszewski
- Center for Addictive Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, 8001 Zurich, Switzerland;
| | - Holger Prokisch
- Institute of Human Genetics, Technical University Munich, 81675 Munich, Germany;
- Institute of Neurogenomics, Helmholtz Zentrum Munich, 85764 Neuherberg, Germany
| | - Thomas Klopstock
- Department of Neurology, Friedrich-Baur-Institute, University of Munich, 80336 Munich, Germany;
- German Center for Neurodegenerative Diseases (DZNE), 81675 Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), 81675 Munich, Germany
| | - Marta Murgia
- Department of Proteomics a Signal Transduction, Max Planck Institute of Biochemistry, 82352 Martinsried, Germany
- Department of Biomedical Sciences, University of Padova, 35131 Padua, Italy
- Correspondence:
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23
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Nisar H, Wajid B, Shahid S, Anwar F, Wajid I, Khatoon A, Sattar MU, Sadaf S. Whole-genome sequencing as a first-tier diagnostic framework for rare genetic diseases. Exp Biol Med (Maywood) 2021; 246:2610-2617. [PMID: 34521224 DOI: 10.1177/15353702211040046] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Rare diseases affect nearly 300 million people globally with most patients aged five or less. Traditional diagnostic approaches have provided much of the diagnosis; however, there are limitations. For instance, simply inadequate and untimely diagnosis adversely affects both the patient and their families. This review advocates the use of whole genome sequencing in clinical settings for diagnosis of rare genetic diseases by showcasing five case studies. These examples specifically describe the utilization of whole genome sequencing, which helped in providing relief to patients via correct diagnosis followed by use of precision medicine.
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Affiliation(s)
- Haseeb Nisar
- Office of Research, Innovation and Commercialization, University of Management and Technology, Lahore 54000, Pakistan.,School of Biochemistry & Biotechnology, University of the Punjab, Lahore 54000, Pakistan
| | - Bilal Wajid
- Department of Electrical Engineering, University of Engineering and Technology, Lahore 54000, Pakistan.,Ibn Sina Research & Development Division, Sabz-Qalam, Lahore 54000, Pakistan.,Department of Computer Sciences, University of Management and Technology, Lahore 54000, Pakistan
| | - Samiah Shahid
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54000, Pakistan
| | - Faria Anwar
- Out Patient Department, Mayo Hospital, Lahore 54000, Pakistan
| | - Imran Wajid
- Ibn Sina Research & Development Division, Sabz-Qalam, Lahore 54000, Pakistan
| | - Asia Khatoon
- School of Biochemistry & Biotechnology, University of the Punjab, Lahore 54000, Pakistan
| | - Mian Usman Sattar
- Institute of Social Sciences, Istanbul Commerce University, Istanbul, Turkey
| | - Saima Sadaf
- School of Biochemistry & Biotechnology, University of the Punjab, Lahore 54000, Pakistan
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24
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Sarkar S, Nambiar M. G-quadruplexes in the mitochondrial genome - a cause for instability. FEBS J 2021; 289:117-120. [PMID: 34405539 DOI: 10.1111/febs.16149] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 08/03/2021] [Indexed: 11/28/2022]
Abstract
Accumulation of mutations such as deletions in mitochondrial DNA is associated with ageing, cancer and human genetic disorders. These deletions are often flanked by GC-skewed sequence motifs that can potentially fold into secondary non-B DNA conformations. G-quadruplexes are emerging as key initiators of mitochondrial genomic instability. In this issue, Dahal et al provide an in silico analysis of sequence motifs that can fold into altered DNA structures in mitochondrial genomic regions that contain frequent deletions. They show the formation of five G-quadruplexes near such frequent breakpoints using biochemical and biophysical approaches in vitro and more importantly inside mammalian cells. Comment on: https://doi.org/10.1111/febs.16113.
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Affiliation(s)
- Sneha Sarkar
- Department of Biology, Indian Institute of Science Education and Research, Pune, India
| | - Mridula Nambiar
- Department of Biology, Indian Institute of Science Education and Research, Pune, India
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25
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Paß T, Wiesner RJ, Pla-Martín D. Selective Neuron Vulnerability in Common and Rare Diseases-Mitochondria in the Focus. Front Mol Biosci 2021; 8:676187. [PMID: 34295920 PMCID: PMC8290884 DOI: 10.3389/fmolb.2021.676187] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022] Open
Abstract
Mitochondrial dysfunction is a central feature of neurodegeneration within the central and peripheral nervous system, highlighting a strong dependence on proper mitochondrial function of neurons with especially high energy consumptions. The fitness of mitochondria critically depends on preservation of distinct processes, including the maintenance of their own genome, mitochondrial dynamics, quality control, and Ca2+ handling. These processes appear to be differently affected in common neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, as well as in rare neurological disorders, including Huntington’s disease, Amyotrophic Lateral Sclerosis and peripheral neuropathies. Strikingly, particular neuron populations of different morphology and function perish in these diseases, suggesting that cell-type specific factors contribute to the vulnerability to distinct mitochondrial defects. Here we review the disruption of mitochondrial processes in common as well as in rare neurological disorders and its impact on selective neurodegeneration. Understanding discrepancies and commonalities regarding mitochondrial dysfunction as well as individual neuronal demands will help to design new targets and to make use of already established treatments in order to improve treatment of these diseases.
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Affiliation(s)
- Thomas Paß
- Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of Cologne, Cologne, Germany
| | - Rudolf J Wiesner
- Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of Cologne, Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - David Pla-Martín
- Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, University of Cologne, Cologne, Germany
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26
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Tang C, Cai J, Yin XM, Weinberg JM, Venkatachalam MA, Dong Z. Mitochondrial quality control in kidney injury and repair. Nat Rev Nephrol 2021; 17:299-318. [PMID: 33235391 PMCID: PMC8958893 DOI: 10.1038/s41581-020-00369-0] [Citation(s) in RCA: 306] [Impact Index Per Article: 76.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2020] [Indexed: 01/30/2023]
Abstract
Mitochondria are essential for the activity, function and viability of eukaryotic cells and mitochondrial dysfunction is involved in the pathogenesis of acute kidney injury (AKI) and chronic kidney disease, as well as in abnormal kidney repair after AKI. Multiple quality control mechanisms, including antioxidant defence, protein quality control, mitochondrial DNA repair, mitochondrial dynamics, mitophagy and mitochondrial biogenesis, have evolved to preserve mitochondrial homeostasis under physiological and pathological conditions. Loss of these mechanisms may induce mitochondrial damage and dysfunction, leading to cell death, tissue injury and, potentially, organ failure. Accumulating evidence suggests a role of disturbances in mitochondrial quality control in the pathogenesis of AKI, incomplete or maladaptive kidney repair and chronic kidney disease. Moreover, specific interventions that target mitochondrial quality control mechanisms to preserve and restore mitochondrial function have emerged as promising therapeutic strategies to prevent and treat kidney injury and accelerate kidney repair. However, clinical translation of these findings is challenging owing to potential adverse effects, unclear mechanisms of action and a lack of knowledge of the specific roles and regulation of mitochondrial quality control mechanisms in kidney resident and circulating cell types during injury and repair of the kidney.
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Affiliation(s)
- Chengyuan Tang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, China
| | - Juan Cai
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, China
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Joel M. Weinberg
- Department of Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Manjeri A. Venkatachalam
- Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Zheng Dong
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, China.,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA.,
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27
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Lakshmanan LN, Yee Z, Halliwell B, Gruber J, Gunawan R. Thermodynamic analysis of DNA hybridization signatures near mitochondrial DNA deletion breakpoints. iScience 2021; 24:102138. [PMID: 33665557 PMCID: PMC7900216 DOI: 10.1016/j.isci.2021.102138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 01/14/2021] [Accepted: 01/29/2021] [Indexed: 11/17/2022] Open
Abstract
Broad evidence in the literature supports double-strand breaks (DSBs) as initiators of mitochondrial DNA (mtDNA) deletion mutations. While DNA misalignment during DSB repair is commonly proposed as the mechanism by which DSBs cause deletion mutations, details such as the specific DNA repair errors are still lacking. Here, we used DNA hybridization thermodynamics to infer the sequence lengths of mtDNA misalignments that are associated with mtDNA deletions. We gathered and analyzed 9,921 previously reported mtDNA deletion breakpoints in human, rhesus monkey, mouse, rat, and Caenorhabditis elegans. Our analysis shows that a large fraction of mtDNA breakpoint positions can be explained by the thermodynamics of short ≤ 5-nt misalignments. The significance of short DNA misalignments supports an important role for erroneous non-homologous and micro-homology-dependent DSB repair in mtDNA deletion formation. The consistency of the results of our analysis across species further suggests a shared mode of mtDNA deletion mutagenesis.
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Affiliation(s)
- Lakshmi Narayanan Lakshmanan
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
- Institute for Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland
| | - Zhuangli Yee
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore
| | - Barry Halliwell
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jan Gruber
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Ageing Research Laboratory, Science Division, Yale-NUS College, Singapore, Singapore
| | - Rudiyanto Gunawan
- Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY, USA
- Corresponding author
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28
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Lee Y, Kim T, Lee M, So S, Karagozlu MZ, Seo GH, Choi IH, Lee PCW, Kim CJ, Kang E, Lee BH. De Novo Development of mtDNA Deletion Due to Decreased POLG and SSBP1 Expression in Humans. Genes (Basel) 2021; 12:genes12020284. [PMID: 33671400 PMCID: PMC7922481 DOI: 10.3390/genes12020284] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 02/10/2021] [Accepted: 02/14/2021] [Indexed: 02/07/2023] Open
Abstract
Defects in the mitochondrial genome (mitochondrial DNA (mtDNA)) are associated with both congenital and acquired disorders in humans. Nuclear-encoded DNA polymerase subunit gamma (POLG) plays an important role in mtDNA replication, and proofreading and mutations in POLG have been linked with increased mtDNA deletions. SSBP1 is also a crucial gene for mtDNA replication. Here, we describe a patient diagnosed with Pearson syndrome with large mtDNA deletions that were not detected in the somatic cells of the mother. Exome sequencing was used to evaluate the nuclear factors associated with the patient and his family, which revealed a paternal POLG mutation (c.868C > T) and a maternal SSBP1 mutation (c.320G > A). The patient showed lower POLG and SSBP1 expression than his healthy brothers and the general population of a similar age. Notably, c.868C in the wild-type allele was highly methylated in the patient compared to the same site in both his healthy brothers. These results suggest that the co- deficient expression of POLG and SSBP1 genes could contribute to the development of mtDNA deletion.
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Affiliation(s)
- Yeonmi Lee
- Department of Convergence Medicine and Stem Cell Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (Y.L.); (M.L.); (S.S.); (M.Z.K.)
| | - Taeho Kim
- Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (T.K.); (G.H.S.); (I.H.C.)
| | - Miju Lee
- Department of Convergence Medicine and Stem Cell Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (Y.L.); (M.L.); (S.S.); (M.Z.K.)
| | - Seongjun So
- Department of Convergence Medicine and Stem Cell Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (Y.L.); (M.L.); (S.S.); (M.Z.K.)
| | - Mustafa Zafer Karagozlu
- Department of Convergence Medicine and Stem Cell Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (Y.L.); (M.L.); (S.S.); (M.Z.K.)
| | - Go Hun Seo
- Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (T.K.); (G.H.S.); (I.H.C.)
| | - In Hee Choi
- Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (T.K.); (G.H.S.); (I.H.C.)
| | - Peter C. W. Lee
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Chong-Jai Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Eunju Kang
- Department of Convergence Medicine and Stem Cell Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (Y.L.); (M.L.); (S.S.); (M.Z.K.)
- Correspondence: (E.K.); (B.H.L.); Tel.: +82-2-3010-8547 (E.K.); +82-2-3010-5950 (B.H.L.)
| | - Beom Hee Lee
- Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (T.K.); (G.H.S.); (I.H.C.)
- Correspondence: (E.K.); (B.H.L.); Tel.: +82-2-3010-8547 (E.K.); +82-2-3010-5950 (B.H.L.)
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29
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Antipova VN. A New Deletion of Mitochondrial DNA of a BALB/c Mouse. RUSS J GENET+ 2021. [DOI: 10.1134/s1022795421020022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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30
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Kumar PR, Moore JA, Bowles KM, Rushworth SA, Moncrieff MD. Mitochondrial oxidative phosphorylation in cutaneous melanoma. Br J Cancer 2021; 124:115-123. [PMID: 33204029 PMCID: PMC7782830 DOI: 10.1038/s41416-020-01159-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 12/14/2022] Open
Abstract
The Warburg effect in tumour cells is associated with the upregulation of glycolysis to generate ATP, even under normoxic conditions and the presence of fully functioning mitochondria. However, scientific advances made over the past 15 years have reformed this perspective, demonstrating the importance of oxidative phosphorylation (OXPHOS) as well as glycolysis in malignant cells. The metabolic phenotypes in melanoma display heterogeneic dynamism (metabolic plasticity) between glycolysis and OXPHOS, conferring a survival advantage to adapt to harsh conditions and pathways of chemoresistance. Furthermore, the simultaneous upregulation of both OXPHOS and glycolysis (metabolic symbiosis) has been shown to be vital for melanoma progression. The tumour microenvironment (TME) has an essential supporting role in promoting progression, invasion and metastasis of melanoma. Mesenchymal stromal cells (MSCs) in the TME show a symbiotic relationship with melanoma, protecting tumour cells from apoptosis and conferring chemoresistance. With the significant role of OXPHOS in metabolic plasticity and symbiosis, our review outlines how mitochondrial transfer from MSCs to melanoma tumour cells plays a key role in melanoma progression and is the mechanism by which melanoma cells regain OXPHOS capacity even in the presence of mitochondrial mutations. The studies outlined in this review indicate that targeting mitochondrial trafficking is a potential novel therapeutic approach for this highly refractory disease.
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Affiliation(s)
- Prakrit R Kumar
- Bob Champion Research and Education Building, Norwich Medical School, University of East Anglia, Norwich, UK
| | - Jamie A Moore
- Bob Champion Research and Education Building, Norwich Medical School, University of East Anglia, Norwich, UK
| | - Kristian M Bowles
- Bob Champion Research and Education Building, Norwich Medical School, University of East Anglia, Norwich, UK
- Department of Haematology, Norfolk and Norwich University Hospital, Norwich, UK
| | - Stuart A Rushworth
- Bob Champion Research and Education Building, Norwich Medical School, University of East Anglia, Norwich, UK.
| | - Marc D Moncrieff
- Bob Champion Research and Education Building, Norwich Medical School, University of East Anglia, Norwich, UK.
- Department of Plastic and Reconstructive Surgery, Norfolk and Norwich University Hospital, Norwich, NR4 7UY, UK.
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31
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Fontana GA, Gahlon HL. Mechanisms of replication and repair in mitochondrial DNA deletion formation. Nucleic Acids Res 2020; 48:11244-11258. [PMID: 33021629 PMCID: PMC7672454 DOI: 10.1093/nar/gkaa804] [Citation(s) in RCA: 135] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/07/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
Deletions in mitochondrial DNA (mtDNA) are associated with diverse human pathologies including cancer, aging and mitochondrial disorders. Large-scale deletions span kilobases in length and the loss of these associated genes contributes to crippled oxidative phosphorylation and overall decline in mitochondrial fitness. There is not a united view for how mtDNA deletions are generated and the molecular mechanisms underlying this process are poorly understood. This review discusses the role of replication and repair in mtDNA deletion formation as well as nucleic acid motifs such as repeats, secondary structures, and DNA damage associated with deletion formation in the mitochondrial genome. We propose that while erroneous replication and repair can separately contribute to deletion formation, crosstalk between these pathways is also involved in generating deletions.
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Affiliation(s)
- Gabriele A Fontana
- Department of Health Sciences and Technology, ETH Zürich, Schmelzbergstrasse 9, 8092 Zürich, Switzerland
| | - Hailey L Gahlon
- To whom correspondence should be addressed. Tel: +41 44 632 3731;
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Allegra AG, Mannino F, Innao V, Musolino C, Allegra A. Radioprotective Agents and Enhancers Factors. Preventive and Therapeutic Strategies for Oxidative Induced Radiotherapy Damages in Hematological Malignancies. Antioxidants (Basel) 2020; 9:antiox9111116. [PMID: 33198328 PMCID: PMC7696711 DOI: 10.3390/antiox9111116] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/08/2020] [Accepted: 11/10/2020] [Indexed: 12/13/2022] Open
Abstract
Radiation therapy plays a critical role in the management of a wide range of hematologic malignancies. It is well known that the post-irradiation damages both in the bone marrow and in other organs are the main causes of post-irradiation morbidity and mortality. Tumor control without producing extensive damage to the surrounding normal cells, through the use of radioprotectors, is of special clinical relevance in radiotherapy. An increasing amount of data is helping to clarify the role of oxidative stress in toxicity and therapy response. Radioprotective agents are substances that moderate the oxidative effects of radiation on healthy normal tissues while preserving the sensitivity to radiation damage in tumor cells. As well as the substances capable of carrying out a protective action against the oxidative damage caused by radiotherapy, other substances have been identified as possible enhancers of the radiotherapy and cytotoxic activity via an oxidative effect. The purpose of this review was to examine the data in the literature on the possible use of old and new substances to increase the efficacy of radiation treatment in hematological diseases and to reduce the harmful effects of the treatment.
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Affiliation(s)
- Andrea Gaetano Allegra
- Radiation Oncology Unit, Department of Biomedical, Experimental, and Clinical Sciences “Mario Serio”, Azienda Ospedaliero-Universitaria Careggi, University of Florence, 50100 Florence, Italy;
| | - Federica Mannino
- Department of Clinical and Experimental Medicine, University of Messina, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy;
| | - Vanessa Innao
- Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, Division of Haematology, University of Messina, 98125 Messina, Italy; (V.I.); (C.M.)
| | - Caterina Musolino
- Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, Division of Haematology, University of Messina, 98125 Messina, Italy; (V.I.); (C.M.)
| | - Alessandro Allegra
- Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, Division of Haematology, University of Messina, 98125 Messina, Italy; (V.I.); (C.M.)
- Correspondence: ; Tel.: +39-090-221-2364
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Niu F, Sharma A, Wang Z, Feng L, Muresanu DF, Sahib S, Tian ZR, Lafuente JV, Buzoianu AD, Castellani RJ, Nozari A, Patnaik R, Wiklund L, Sharma HS. Co-administration of TiO 2-nanowired dl-3-n-butylphthalide (dl-NBP) and mesenchymal stem cells enhanced neuroprotection in Parkinson's disease exacerbated by concussive head injury. PROGRESS IN BRAIN RESEARCH 2020; 258:101-155. [PMID: 33223034 DOI: 10.1016/bs.pbr.2020.09.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
dl-3-n-butylphthalide (dl-NBP) is a powerful antioxidant compound with profound neuroprotective effects in stroke and brain injury. However, its role in Parkinson's disease (PD) is not well known. Traumatic brain injury (TBI) is one of the key factors in precipitating PD like symptoms in civilians and particularly in military personnel. Thus, it would be interesting to explore the possible neuroprotective effects of NBP in PD following concussive head injury (CHI). In this chapter effect of nanowired delivery of NBP together with mesenchymal stem cells (MSCs) in PD with CHI is discussed based on our own investigations. It appears that CHI exacerbates PD pathophysiology in terms of p-tau, α-synuclein (ASNC) levels in the cerebrospinal fluid (CSF) and the loss of TH immunoreactivity in substantia niagra pars compacta (SNpc) and striatum (STr) along with dopamine (DA), dopamine decarboxylase (DOPAC). And homovanillic acid (HVA). Our observations are the first to show that a combination of NBP with MSCs when delivered using nanowired technology induces superior neuroprotective effects in PD brain pathology exacerbated by CHI, not reported earlier.
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Affiliation(s)
- Feng Niu
- CSPC NBP Pharmaceutical Medicine, Shijiazhuang, Hebei Province, China
| | - Aruna Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
| | - Zhenguo Wang
- CSPC NBP Pharmaceutical Medicine, Shijiazhuang, Hebei Province, China
| | - Lianyuan Feng
- Department of Neurology, Bethune International Peace Hospital, Shijiazhuang, Hebei Province, China
| | - Dafin F Muresanu
- Department of Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania; "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania
| | - Seaab Sahib
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - Z Ryan Tian
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - José Vicente Lafuente
- LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
| | - Anca D Buzoianu
- Department of Clinical Pharmacology and Toxicology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Rudy J Castellani
- Department of Pathology, University of Maryland, Baltimore, MD, United States
| | - Ala Nozari
- Anesthesiology & Intensive Care, Massachusetts General Hospital, Boston, MA, United States
| | - Ranjana Patnaik
- Department of Biomaterials, School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, India
| | - Lars Wiklund
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
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34
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Bagge EK, Fujimori-Tonou N, Kubota-Sakashita M, Kasahara T, Kato T. Unbiased PCR-free spatio-temporal mapping of the mtDNA mutation spectrum reveals brain region-specific responses to replication instability. BMC Biol 2020; 18:150. [PMID: 33097039 PMCID: PMC7585204 DOI: 10.1186/s12915-020-00890-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 10/06/2020] [Indexed: 12/24/2022] Open
Abstract
Background The accumulation of mtDNA mutations in different tissues from various mouse models has been widely studied especially in the context of mtDNA mutation-driven ageing but has been confounded by the inherent limitations of the most widely used approaches. By implementing a method to sequence mtDNA without PCR amplification prior to library preparation, we map the full unbiased mtDNA mutation spectrum across six distinct brain regions from mice. Results We demonstrate that ageing-induced levels of mtDNA mutations (single nucleotide variants and deletions) reach stable levels at 50 weeks of age but can be further elevated specifically in the cortex, nucleus accumbens (NAc), and paraventricular thalamic nucleus (PVT) by expression of a proof-reading-deficient mitochondrial DNA polymerase, PolgD181A. The increase in single nucleotide variants increases the fraction of shared SNVs as well as their frequency, while characteristics of deletions remain largely unaffected. In addition, PolgD181A also induces an ageing-dependent accumulation of non-coding control-region multimers in NAc and PVT, a feature that appears almost non-existent in wild-type mice. Conclusions Our data provide a novel view of the spatio-temporal accumulation of mtDNA mutations using very limited tissue input. The differential response of brain regions to a state of replication instability provides insight into a possible heterogenic mitochondrial landscape across the brain that may be involved in the ageing phenotype and mitochondria-associated disorders.
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Affiliation(s)
- Emilie Kristine Bagge
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Noriko Fujimori-Tonou
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Saitama, Japan.,Current address: Support Unit for Bio-Material Analysis, Research Resources Division, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Mie Kubota-Sakashita
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Takaoki Kasahara
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Saitama, Japan.,Current address: Career Development Program, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Tadafumi Kato
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Saitama, Japan. .,Department of Psychiatry and Behavioral Science, Juntendo University, Graduate School of Medicine, Hongo 2-1-1, Bunkyo, Tokyo 113-8421, Japan.
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35
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Webb M, Sideris DP. Intimate Relations-Mitochondria and Ageing. Int J Mol Sci 2020; 21:ijms21207580. [PMID: 33066461 PMCID: PMC7589147 DOI: 10.3390/ijms21207580] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 12/14/2022] Open
Abstract
Mitochondrial dysfunction is associated with ageing, but the detailed causal relationship between the two is still unclear. We review the major phenomenological manifestations of mitochondrial age-related dysfunction including biochemical, regulatory and energetic features. We conclude that the complexity of these processes and their inter-relationships are still not fully understood and at this point it seems unlikely that a single linear cause and effect relationship between any specific aspect of mitochondrial biology and ageing can be established in either direction.
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Affiliation(s)
- Michael Webb
- Mitobridge Inc., an Astellas Company, 1030 Massachusetts Ave, Cambridge, MA 02138, USA
| | - Dionisia P Sideris
- Mitobridge Inc., an Astellas Company, 1030 Massachusetts Ave, Cambridge, MA 02138, USA
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36
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Lujan SA, Longley MJ, Humble MH, Lavender CA, Burkholder A, Blakely EL, Alston CL, Gorman GS, Turnbull DM, McFarland R, Taylor RW, Kunkel TA, Copeland WC. Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging. Genome Biol 2020; 21:248. [PMID: 32943091 PMCID: PMC7500033 DOI: 10.1186/s13059-020-02138-5] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 08/07/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Acquired human mitochondrial genome (mtDNA) deletions are symptoms and drivers of focal mitochondrial respiratory deficiency, a pathological hallmark of aging and late-onset mitochondrial disease. RESULTS To decipher connections between these processes, we create LostArc, an ultrasensitive method for quantifying deletions in circular mtDNA molecules. LostArc reveals 35 million deletions (~ 470,000 unique spans) in skeletal muscle from 22 individuals with and 19 individuals without pathogenic variants in POLG. This nuclear gene encodes the catalytic subunit of replicative mitochondrial DNA polymerase γ. Ablation, the deleted mtDNA fraction, suffices to explain skeletal muscle phenotypes of aging and POLG-derived disease. Unsupervised bioinformatic analyses reveal distinct age- and disease-correlated deletion patterns. CONCLUSIONS These patterns implicate replication by DNA polymerase γ as the deletion driver and suggest little purifying selection against mtDNA deletions by mitophagy in postmitotic muscle fibers. Observed deletion patterns are best modeled as mtDNA deletions initiated by replication fork stalling during strand displacement mtDNA synthesis.
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Affiliation(s)
- Scott A Lujan
- Genome Integrity and Structural Biology Laboratory, DNA Replication Fidelity Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA
| | - Matthew J Longley
- Genome Integrity and Structural Biology Laboratory, Mitochondrial DNA Replication Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA
| | - Margaret H Humble
- Genome Integrity and Structural Biology Laboratory, Mitochondrial DNA Replication Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA
| | - Christopher A Lavender
- Integrative Bioinformatics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA
| | - Adam Burkholder
- Integrative Bioinformatics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA
| | - Emma L Blakely
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
- NHS Highly Specialised Mitochondrial Diagnostic Laboratory, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK
| | - Charlotte L Alston
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
- NHS Highly Specialised Mitochondrial Diagnostic Laboratory, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK
| | - Grainne S Gorman
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Doug M Turnbull
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Robert McFarland
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Robert W Taylor
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
- NHS Highly Specialised Mitochondrial Diagnostic Laboratory, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK
| | - Thomas A Kunkel
- Genome Integrity and Structural Biology Laboratory, DNA Replication Fidelity Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA
| | - William C Copeland
- Genome Integrity and Structural Biology Laboratory, Mitochondrial DNA Replication Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.
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37
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Mohamed Yusoff AA, Mohd Khair SZN, Abd Radzak SM, Idris Z, Lee HC. Prevalence of mitochondrial DNA common deletion in patients with gliomas and meningiomas: A first report from a Malaysian study group. J Chin Med Assoc 2020; 83:838-844. [PMID: 32732530 PMCID: PMC7478208 DOI: 10.1097/jcma.0000000000000401] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The 4977-bp common deletion (mtDNA) is a well-established mitochondrial genome alteration that has been described in various types of human cancers. However, to date, no studies on mtDNA in brain tumors have been reported. The present study aimed to determine mtDNA prevalence in common brain tumors, specifically, low- and high-grade gliomas (LGGs and HGGs), and meningiomas in Malaysian cases. Its correlation with clinicopathological parameters was also evaluated. METHODS A total of 50 patients with pathologically confirmed brain tumors (13 LGGs, 20 HGGs, and 17 meningiomas) were enrolled in this study. mtDNA was detected by using polymerase chain reaction (PCR) technique and later confirmed via Sanger DNA sequencing. RESULTS Overall, mtDNA was observed in 16 (32%) patients and it was significantly correlated with the type of tumor group and sex, being more common in the HGG group and in male patients. CONCLUSION The prevalence of mtDNA in Malaysian glioma and meningioma cases has been described for the first time and it was, indeed, comparable with previously published studies. This study provides initial insights into mtDNA in brain tumor and these findings can serve as new data for the global mitochondrial DNA mutations database.
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Affiliation(s)
- Abdul Aziz Mohamed Yusoff
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
- Address correspondence. Dr. Abdul Aziz Mohamed Yusoff, Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia. E-mail address: (A.A. Mohamed Yusoff)
| | - Siti Zulaikha Nashwa Mohd Khair
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
| | - Siti Muslihah Abd Radzak
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
| | - Zamzuri Idris
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
| | - Hsin-Chen Lee
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
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Chapman J, Ng YS, Nicholls TJ. The Maintenance of Mitochondrial DNA Integrity and Dynamics by Mitochondrial Membranes. Life (Basel) 2020; 10:life10090164. [PMID: 32858900 PMCID: PMC7555930 DOI: 10.3390/life10090164] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/20/2020] [Accepted: 08/23/2020] [Indexed: 12/18/2022] Open
Abstract
Mitochondria are complex organelles that harbour their own genome. Mitochondrial DNA (mtDNA) exists in the form of a circular double-stranded DNA molecule that must be replicated, segregated and distributed around the mitochondrial network. Human cells typically possess between a few hundred and several thousand copies of the mitochondrial genome, located within the mitochondrial matrix in close association with the cristae ultrastructure. The organisation of mtDNA around the mitochondrial network requires mitochondria to be dynamic and undergo both fission and fusion events in coordination with the modulation of cristae architecture. The dysregulation of these processes has profound effects upon mtDNA replication, manifesting as a loss of mtDNA integrity and copy number, and upon the subsequent distribution of mtDNA around the mitochondrial network. Mutations within genes involved in mitochondrial dynamics or cristae modulation cause a wide range of neurological disorders frequently associated with defects in mtDNA maintenance. This review aims to provide an understanding of the biological mechanisms that link mitochondrial dynamics and mtDNA integrity, as well as examine the interplay that occurs between mtDNA, mitochondrial dynamics and cristae structure.
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Affiliation(s)
- James Chapman
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Correspondence: (J.C.); (T.J.N.)
| | - Yi Shiau Ng
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Thomas J. Nicholls
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Correspondence: (J.C.); (T.J.N.)
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39
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Licht-Mayer S, Campbell GR, Canizares M, Mehta AR, Gane AB, McGill K, Ghosh A, Fullerton A, Menezes N, Dean J, Dunham J, Al-Azki S, Pryce G, Zandee S, Zhao C, Kipp M, Smith KJ, Baker D, Altmann D, Anderton SM, Kap YS, Laman JD, Hart BA', Rodriguez M, Watzlawick R, Schwab JM, Carter R, Morton N, Zagnoni M, Franklin RJM, Mitchell R, Fleetwood-Walker S, Lyons DA, Chandran S, Lassmann H, Trapp BD, Mahad DJ. Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis. Acta Neuropathol 2020; 140:143-167. [PMID: 32572598 PMCID: PMC7360646 DOI: 10.1007/s00401-020-02179-x] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/25/2020] [Accepted: 06/10/2020] [Indexed: 12/11/2022]
Abstract
Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.
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Affiliation(s)
- Simon Licht-Mayer
- Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
| | - Graham R Campbell
- Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
| | - Marco Canizares
- Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
| | - Arpan R Mehta
- Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
- UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
| | - Angus B Gane
- Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
| | - Katie McGill
- Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
| | - Aniket Ghosh
- Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
| | - Alexander Fullerton
- Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
| | - Niels Menezes
- Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
| | - Jasmine Dean
- Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
| | - Jordon Dunham
- Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, OH44195, USA
| | - Sarah Al-Azki
- Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK
| | - Gareth Pryce
- Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK
| | - Stephanie Zandee
- Centre for Inflammation Research, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4SB, UK
| | - Chao Zhao
- Wellcome Trust-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0AW, UK
| | - Markus Kipp
- Institute of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9, 18057, Rostock, Germany
| | - Kenneth J Smith
- Department of Neuroinflammation, The UCL Queen Square Institute of Neurology, University College London, 1 Wakefield Street, London, WC1N 1PJ, UK
| | - David Baker
- Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK
| | - Daniel Altmann
- Faculty of Medicine, Department of Medicine, Hammersmith Campus, London, UK
| | - Stephen M Anderton
- Centre for Inflammation Research, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4SB, UK
| | - Yolanda S Kap
- Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - Jon D Laman
- Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands
- Dept. Biomedical Sciences of Cells and Systems and MS Center Noord Nederland (MSCNN), University Medical Center Groningen, University Groningen, Groningen, The Netherlands
| | - Bert A 't Hart
- Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands
- Dept. Biomedical Sciences of Cells and Systems and MS Center Noord Nederland (MSCNN), University Medical Center Groningen, University Groningen, Groningen, The Netherlands
- Department Anatomy and Neuroscience, Amsterdam University Medical Center (V|UMC|), Amsterdam, Netherlands
| | - Moses Rodriguez
- Department of Neurology and Immunology, Mayo College of Medicine and Science, Rochester, MN, MN55905, USA
| | - Ralf Watzlawick
- Department of Neurosurgery, Freiburg University Medical Center, Freiburg, Germany
| | - Jan M Schwab
- Spinal Cord Injury Medicine, Department of Neurology, The Ohio State University, Wexner Medical Center, Columbus, USA
| | - Roderick Carter
- Centre for Cardiovascular Science, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh, UK
| | - Nicholas Morton
- Centre for Cardiovascular Science, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh, UK
| | - Michele Zagnoni
- Centre for Microsystems and Photonics, Electronic and Electrical Engineering, University of Strathclyde, Glasgow, UK
| | - Robin J M Franklin
- Wellcome Trust-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0AW, UK
| | - Rory Mitchell
- Centre for Discovery Brain Science, Edinburgh Medical School, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
| | - Sue Fleetwood-Walker
- Centre for Discovery Brain Science, Edinburgh Medical School, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
| | - David A Lyons
- Centre for Discovery Brain Science, Edinburgh Medical School, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
| | - Siddharthan Chandran
- Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
- UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
| | - Hans Lassmann
- Department of Neuroimmunology, Center for Brain Research, Medical University Vienna, Spitalgasse 4, 1090, Vienna, Austria
| | - Bruce D Trapp
- Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, OH44195, USA
| | - Don J Mahad
- Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
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40
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Abstract
Maternally mitochondrial dysfunction includes a heterogeneous group of genetic disorders which leads to the impairment of the final common pathway of energy metabolism. Coronary heart disease and coronary venous disease are two important clinical manifestations of mitochondrial dysfunction due to abnormality in the setting of underlying pathways. Mitochondrial dysfunction can lead to cardiomyopathy, which is involved in the onset of acute cardiac and pulmonary failure. Mitochondrial diseases present other cardiac manifestations such as left ventricular noncompaction and cardiac conduction disease. Different clinical findings from mitochondrial dysfunction originate from different mtDNA mutations, and this variety of clinical symptoms poses a diagnostic challenge for cardiologists. Heart transplantation may be a good treatment, but it is not always possible, and other complications of the disease, such as mitochondrial encephalopathy, lactic acidosis, and stroke-like syndrome, should be considered. To diagnose and treat most mitochondrial disorders, careful cardiac, neurological, and molecular studies are needed. In this study, we looked at molecular genetics of MIDs and cardiac manifestations in patients with mitochondrial dysfunction.
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41
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Zhao L, Sumberaz P. Mitochondrial DNA Damage: Prevalence, Biological Consequence, and Emerging Pathways. Chem Res Toxicol 2020; 33:2491-2502. [PMID: 32486637 DOI: 10.1021/acs.chemrestox.0c00083] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mitochondria have a plethora of functions within a eukaryotic cell, ranging from energy production, cell signaling, and protein cofactor synthesis to various aspects of metabolism. Mitochondrial dysfunction is known to cause over 200 named disorders and has been implicated in many human diseases and aging. Mitochondria have their own genetic material, mitochondrial DNA (mtDNA), which encodes 13 protein subunits in the oxidative phosphorylation system and a full set of transfer and rRNAs. Although more than 99% of the proteins in mitochondria are nuclear DNA (nDNA)-encoded, the integrity of mtDNA is critical for mitochondrial functions, as evidenced by mitochondrial diseases sourced from mtDNA mutations and depletions and the vital role of fragmented mtDNA molecules in cell signaling pathways. Previous research has shown that mtDNA is an important target of genotoxic assaults by a variety of chemical and physical factors. This Perspective discusses the prevalence of mtDNA damage by comparing the abundance of lesions in mDNA and nDNA and summarizes current knowledge on the biological pathways to cope with mtDNA damage, including mtDNA repair, mtDNA degradation, and mitochondrial fission and fusion. Also, emerging roles of mtDNA damage in mutagenesis and immune responses are reviewed.
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Affiliation(s)
- Linlin Zhao
- Department of Chemistry and Environmental Toxicology Graduate Program, University of California, Riverside, Riverside, California 92521, United States
| | - Philip Sumberaz
- Department of Chemistry and Environmental Toxicology Graduate Program, University of California, Riverside, Riverside, California 92521, United States
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42
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Lawless C, Greaves L, Reeve AK, Turnbull DM, Vincent AE. The rise and rise of mitochondrial DNA mutations. Open Biol 2020; 10:200061. [PMID: 32428418 PMCID: PMC7276526 DOI: 10.1098/rsob.200061] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 04/23/2020] [Indexed: 12/24/2022] Open
Abstract
How mitochondrial DNA mutations clonally expand in an individual cell is a question that has perplexed mitochondrial biologists for decades. A growing body of literature indicates that mitochondrial DNA mutations play a major role in ageing, metabolic diseases, neurodegenerative diseases, neuromuscular disorders and cancers. Importantly, this process of clonal expansion occurs for both inherited and somatic mitochondrial DNA mutations. To complicate matters further there are fundamental differences between mitochondrial DNA point mutations and deletions, and between mitotic and post-mitotic cells, that impact this pathogenic process. These differences, along with the challenges of investigating a longitudinal process occurring over decades in humans, have so far hindered progress towards understanding clonal expansion. Here we summarize our current understanding of the clonal expansion of mitochondrial DNA mutations in different tissues and highlight key unanswered questions. We then discuss the various existing biological models, along with their advantages and disadvantages. Finally, we explore what has been achieved with mathematical modelling so far and suggest future work to advance this important area of research.
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Affiliation(s)
| | | | | | - Doug M. Turnbull
- Wellcome Centre for Mitochondrial Research, Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle NE2 4HH, UK
| | - Amy E. Vincent
- Wellcome Centre for Mitochondrial Research, Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle NE2 4HH, UK
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43
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Kaur P, Longley MJ, Pan H, Wang W, Countryman P, Wang H, Copeland WC. Single-molecule level structural dynamics of DNA unwinding by human mitochondrial Twinkle helicase. J Biol Chem 2020; 295:5564-5576. [PMID: 32213598 PMCID: PMC7186178 DOI: 10.1074/jbc.ra120.012795] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/24/2020] [Indexed: 11/06/2022] Open
Abstract
Knowledge of the molecular events in mitochondrial DNA (mtDNA) replication is crucial to understanding the origins of human disorders arising from mitochondrial dysfunction. Twinkle helicase is an essential component of mtDNA replication. Here, we employed atomic force microscopy imaging in air and liquids to visualize ring assembly, DNA binding, and unwinding activity of individual Twinkle hexamers at the single-molecule level. We observed that the Twinkle subunits self-assemble into hexamers and higher-order complexes that can switch between open and closed-ring configurations in the absence of DNA. Our analyses helped visualize Twinkle loading onto and unloading from DNA in an open-ringed configuration. They also revealed that closed-ring conformers bind and unwind several hundred base pairs of duplex DNA at an average rate of ∼240 bp/min. We found that the addition of mitochondrial single-stranded (ss) DNA-binding protein both influences the ways Twinkle loads onto defined DNA substrates and stabilizes the unwound ssDNA product, resulting in a ∼5-fold stimulation of the apparent DNA-unwinding rate. Mitochondrial ssDNA-binding protein also increased the estimated translocation processivity from 1750 to >9000 bp before helicase disassociation, suggesting that more than half of the mitochondrial genome could be unwound by Twinkle during a single DNA-binding event. The strategies used in this work provide a new platform to examine Twinkle disease variants and the core mtDNA replication machinery. They also offer an enhanced framework to investigate molecular mechanisms underlying deletion and depletion of the mitochondrial genome as observed in mitochondrial diseases.
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Affiliation(s)
- Parminder Kaur
- Physics Department, North Carolina State University, Raleigh, North Carolina 27695; Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina 27695.
| | - Matthew J Longley
- Genome Integrity and Structural Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709
| | - Hai Pan
- Physics Department, North Carolina State University, Raleigh, North Carolina 27695
| | - Wendy Wang
- Physics Department, North Carolina State University, Raleigh, North Carolina 27695
| | - Preston Countryman
- Physics Department, North Carolina State University, Raleigh, North Carolina 27695
| | - Hong Wang
- Physics Department, North Carolina State University, Raleigh, North Carolina 27695; Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina 27695; Toxicology Program, North Carolina State University, Raleigh, North Carolina 27695
| | - William C Copeland
- Genome Integrity and Structural Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
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44
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Peter B, Falkenberg M. TWINKLE and Other Human Mitochondrial DNA Helicases: Structure, Function and Disease. Genes (Basel) 2020; 11:genes11040408. [PMID: 32283748 PMCID: PMC7231222 DOI: 10.3390/genes11040408] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 12/30/2022] Open
Abstract
Mammalian mitochondria contain a circular genome (mtDNA) which encodes subunits of the oxidative phosphorylation machinery. The replication and maintenance of mtDNA is carried out by a set of nuclear-encoded factors—of which, helicases form an important group. The TWINKLE helicase is the main helicase in mitochondria and is the only helicase required for mtDNA replication. Mutations in TWINKLE cause a number of human disorders associated with mitochondrial dysfunction, neurodegeneration and premature ageing. In addition, a number of other helicases with a putative role in mitochondria have been identified. In this review, we discuss our current knowledge of TWINKLE structure and function and its role in diseases of mtDNA maintenance. We also briefly discuss other potential mitochondrial helicases and postulate on their role(s) in mitochondria.
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45
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Oliveira MT, Pontes CDB, Ciesielski GL. Roles of the mitochondrial replisome in mitochondrial DNA deletion formation. Genet Mol Biol 2020; 43:e20190069. [PMID: 32141473 PMCID: PMC7197994 DOI: 10.1590/1678-4685-gmb-2019-0069] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Accepted: 08/12/2019] [Indexed: 01/07/2023] Open
Abstract
Mitochondrial DNA (mtDNA) deletions are a common cause of human mitochondrial
diseases. Mutations in the genes encoding components of the mitochondrial
replisome, such as DNA polymerase gamma (Pol γ) and the mtDNA helicase Twinkle,
have been associated with the accumulation of such deletions and the development
of pathological conditions in humans. Recently, we demonstrated that changes in
the level of wild-type Twinkle promote mtDNA deletions, which implies that not
only mutations in, but also dysregulation of the stoichiometry between the
replisome components is potentially pathogenic. The mechanism(s) by which
alterations to the replisome function generate mtDNA deletions is(are) currently
under debate. It is commonly accepted that stalling of the replication fork at
sites likely to form secondary structures precedes the deletion formation. The
secondary structural elements can be bypassed by the replication-slippage
mechanism. Otherwise, stalling of the replication fork can generate single- and
double-strand breaks, which can be repaired through recombination leading to the
elimination of segments between the recombination sites. Here, we discuss
aberrances of the replisome in the context of the two debated outcomes, and
suggest new mechanistic explanations based on replication restart and template
switching that could account for all the deletion types reported for
patients.
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Affiliation(s)
- Marcos T Oliveira
- Universidade Estadual Paulista Júlio de Mesquita Filho, Faculdade de Ciências Agrárias e Veterinárias, Departamento de Tecnologia, Jaboticabal, SP, Brazil
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46
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Dard L, Blanchard W, Hubert C, Lacombe D, Rossignol R. Mitochondrial functions and rare diseases. Mol Aspects Med 2020; 71:100842. [PMID: 32029308 DOI: 10.1016/j.mam.2019.100842] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 12/26/2019] [Accepted: 12/27/2019] [Indexed: 12/19/2022]
Abstract
Mitochondria are dynamic cellular organelles responsible for a large variety of biochemical processes as energy transduction, REDOX signaling, the biosynthesis of hormones and vitamins, inflammation or cell death execution. Cell biology studies established that 1158 human genes encode proteins localized to mitochondria, as registered in MITOCARTA. Clinical studies showed that a large number of these mitochondrial proteins can be altered in expression and function through genetic, epigenetic or biochemical mechanisms including the interaction with environmental toxics or iatrogenic medicine. As a result, pathogenic mitochondrial genetic and functional defects participate to the onset and the progression of a growing number of rare diseases. In this review we provide an exhaustive survey of the biochemical, genetic and clinical studies that demonstrated the implication of mitochondrial dysfunction in human rare diseases. We discuss the striking diversity of the symptoms caused by mitochondrial dysfunction and the strategies proposed for mitochondrial therapy, including a survey of ongoing clinical trials.
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Affiliation(s)
- L Dard
- Bordeaux University, 33000, Bordeaux, France; INSERM U1211, 33000, Bordeaux, France; CELLOMET, CGFB-146 Rue Léo Saignat, Bordeaux, France
| | - W Blanchard
- Bordeaux University, 33000, Bordeaux, France; INSERM U1211, 33000, Bordeaux, France; CELLOMET, CGFB-146 Rue Léo Saignat, Bordeaux, France
| | - C Hubert
- Bordeaux University, 33000, Bordeaux, France; INSERM U1211, 33000, Bordeaux, France
| | - D Lacombe
- Bordeaux University, 33000, Bordeaux, France; INSERM U1211, 33000, Bordeaux, France; CHU de Bordeaux, Service de Génétique Médicale, F-33076, Bordeaux, France
| | - R Rossignol
- Bordeaux University, 33000, Bordeaux, France; INSERM U1211, 33000, Bordeaux, France; CELLOMET, CGFB-146 Rue Léo Saignat, Bordeaux, France.
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47
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Tapias V. Editorial: Mitochondrial Dysfunction and Neurodegeneration. Front Neurosci 2019; 13:1372. [PMID: 31920522 PMCID: PMC6930234 DOI: 10.3389/fnins.2019.01372] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 12/04/2019] [Indexed: 01/17/2023] Open
Affiliation(s)
- Victor Tapias
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States
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48
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Lehmann D, Tuppen HAL, Campbell GE, Alston CL, Lawless C, Rosa HS, Rocha MC, Reeve AK, Nicholls TJ, Deschauer M, Zierz S, Taylor RW, Turnbull DM, Vincent AE. Understanding mitochondrial DNA maintenance disorders at the single muscle fibre level. Nucleic Acids Res 2019; 47:7430-7443. [PMID: 31147703 PMCID: PMC6698645 DOI: 10.1093/nar/gkz472] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 05/12/2019] [Accepted: 05/16/2019] [Indexed: 01/07/2023] Open
Abstract
Clonal expansion of mitochondrial DNA (mtDNA) deletions is an important pathological mechanism in adults with mtDNA maintenance disorders, leading to a mosaic mitochondrial respiratory chain deficiency in skeletal muscle. This study had two aims: (i) to determine if different Mendelian mtDNA maintenance disorders showed similar pattern of mtDNA deletions and respiratory chain deficiency and (ii) to investigate the correlation between the mitochondrial genetic defect and corresponding respiratory chain deficiency. We performed a quantitative analysis of respiratory chain deficiency, at a single cell level, in a cohort of patients with mutations in mtDNA maintenance genes. Using the same tissue section, we performed laser microdissection and single cell genetic analysis to investigate the relationship between mtDNA deletion characteristics and the respiratory chain deficiency. The pattern of respiratory chain deficiency is similar with different genetic defects. We demonstrate a clear correlation between the level of mtDNA deletion and extent of respiratory chain deficiency within a single cell. Long-range and single molecule PCR shows the presence of multiple mtDNA deletions in approximately one-third of all muscle fibres. We did not detect evidence of a replicative advantage for smaller mtDNA molecules in the majority of fibres, but further analysis is needed to provide conclusive evidence.
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Affiliation(s)
- Diana Lehmann
- Department of Neurology, University of Ulm, 89075, Ulm, Germany.,Department of Neurology, University of Halle-Wittenberg, 06120, Halle/Saale, Germany
| | - Helen A L Tuppen
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Georgia E Campbell
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Charlotte L Alston
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.,NHS Highly Specialised Mitochondrial Diagnostic Laboratory, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE2 4HH, UK
| | - Conor Lawless
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Hannah S Rosa
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Mariana C Rocha
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Amy K Reeve
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.,Centre for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Thomas J Nicholls
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Marcus Deschauer
- Department of Neurology, Technical University Munich, 81675, Munich, Germany
| | - Stephan Zierz
- Department of Neurology, University of Halle-Wittenberg, 06120, Halle/Saale, Germany
| | - Robert W Taylor
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.,NHS Highly Specialised Mitochondrial Diagnostic Laboratory, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE2 4HH, UK
| | - Doug M Turnbull
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.,Centre for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Amy E Vincent
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.,Centre for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
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49
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Chinopoulos C. Quantification of mitochondrial DNA from peripheral tissues: Limitations in predicting the severity of neurometabolic disorders and proposal of a novel diagnostic test. Mol Aspects Med 2019; 71:100834. [PMID: 31740079 DOI: 10.1016/j.mam.2019.11.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 11/07/2019] [Accepted: 11/12/2019] [Indexed: 11/25/2022]
Abstract
Neurometabolic disorders stem from errors in metabolic processes yielding a neurological phenotype. A subset of those disorders encompasses mitochondrial abnormalities partially due to mitochondrial DNA (mtDNA) depletion. mtDNA depletion can be attributed to inheritance, spontaneous mutations or acquired from drug-related toxicities. In the armamentarium of diagnostic procedures, mtDNA quantification is a standard for disease classification. However, alterations in mtDNA obtained from peripheral tissues such as skin fibroblasts and blood cells do not often reflect the severity of the affected organ, in this case, the brain. The purpose of this review is to highlight the pitfalls of quantitating mtDNA from peripheral -and not limited to-tissues for diagnosing patients suffering from a variety of mtDNA depletion syndromes exhibiting neurologic abnormalities. In lieu, a qualitative test of mitochondrial substrate-level phosphorylation -even from peripheral tissues-reflecting the ability of mitochondria to rely on glutaminolysis in the presence of respiratory chain defects is proposed as a novel diagnostic assessment of mitochondrial functionality.
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Affiliation(s)
- Christos Chinopoulos
- Department of Medical Biochemistry, Semmelweis University, Tuzolto St. 37-47, Budapest, 1094, Hungary.
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50
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Alteration of mitochondrial DNA homeostasis in drug-induced liver injury. Food Chem Toxicol 2019; 135:110916. [PMID: 31669601 DOI: 10.1016/j.fct.2019.110916] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/21/2019] [Accepted: 10/23/2019] [Indexed: 02/06/2023]
Abstract
Mitochondrial DNA (mtDNA) encodes for 13 proteins involved in the oxidative phosphorylation (OXPHOS) process. In liver, genetic or acquired impairment of mtDNA homeostasis can reduce ATP output but also decrease fatty acid oxidation, thus leading to different hepatic lesions including massive necrosis and microvesicular steatosis. Hence, a severe impairment of mtDNA homeostasis can lead to liver failure and death. An increasing number of investigations report that some drugs can induce mitochondrial dysfunction and drug-induced liver injury (DILI) by altering mtDNA homeostasis. Some drugs such as ciprofloxacin, antiretroviral nucleoside reverse-transcriptase inhibitors and tacrine can inhibit hepatic mtDNA replication, thus inducing mtDNA depletion. Drug-induced reduced mtDNA levels can also be the consequence of reactive oxygen species-mediated oxidative damage to mtDNA, which triggers its degradation by mitochondrial nucleases. Such mechanism is suspected for acetaminophen and troglitazone. Other pharmaceuticals such as linezolid and tetracyclines can impair mtDNA translation, thus selectively reducing the synthesis of the 13 mtDNA-encoded proteins. Lastly, some drugs might alter the mtDNA methylation status but the pathophysiological consequences of such alteration are still unclear. Drug-induced impairment of mtDNA homeostasis is probably under-recognized since preclinical and post-marketing safety studies do not classically investigate mtDNA levels, mitochondrial protein synthesis and mtDNA oxidative damage.
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