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1
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Wang Z, Zhao X, Lu M, Wang N, Xu S, Min D, Wang L. The role of sirtuins in the regulation of reactive oxygen species in myocardial ischemia/reperfusion injury. Mol Cell Biochem 2025; 480:3501-3520. [PMID: 39920412 DOI: 10.1007/s11010-024-05204-9] [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: 09/11/2024] [Accepted: 12/28/2024] [Indexed: 02/09/2025]
Abstract
Myocardial ischemia/reperfusion (I/R) injury has high morbidity and mortality rates, posing a significant burden on society. There is an urgent need to understand its pathogenesis and develop effective treatments. Reactive oxygen species (ROS) are crucial for the development of myocardial I/R injury, and inhibiting ROS overproduction is one of the most critical ways to delay myocardial I/R injury. Sirtuins are a group of nicotinic adenine dinucleotide ( +)-dependent histone deacetylases whose members can regulate ROS by modulating various biological processes. Numerous studies have shown that Sirtuins play an essential role in the progression of myocardial I/R injury by regulating ROS. This study focuses on the relationship between myocardial I/R injury and ROS, Sirtuins and ROS, discusses the role of Sirtuins in regulating ROS in myocardial I/R, and summarizes the therapeutic modalities aimed at targeting Sirtuins to modulate ROS in myocardial I/R injury, thereby guiding future research endeavors.
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Affiliation(s)
- Zheng Wang
- School of Medicine, Qilu Institute of Technology, Jinan, 250200, China
| | - Xiaopeng Zhao
- College of Exercise and Health, Shenyang Sport University, Shenyang, 110102, China
| | - Mingjing Lu
- School of Medicine, Qilu Institute of Technology, Jinan, 250200, China
| | - Naiyu Wang
- School of Medicine, Qilu Institute of Technology, Jinan, 250200, China
| | - Shu Xu
- The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, 110032, China
| | - Dongyu Min
- Experimental Center of Traditional Chinese Medicine, The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, 110032, China.
| | - Lijie Wang
- Department of Cardiology, the Fourth Affiliated Hospital of China Medical University, Shenyang, 110033, China.
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2
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Xie P, Qu T, Tang K, Huang Y, Zeng G, Yuan H, Xin Q, Zhao Y, Yang J, Zeng C, Wu X, Yang ST, Tang X. Carbon nanoparticles-Fe(II) complex combined with sorafenib for ferroptosis-induced antitumor effects in triple-negative breast cancer. Colloids Surf B Biointerfaces 2025; 250:114562. [PMID: 39965484 DOI: 10.1016/j.colsurfb.2025.114562] [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: 11/29/2024] [Revised: 01/27/2025] [Accepted: 02/10/2025] [Indexed: 02/20/2025]
Abstract
Triple negative breast cancer (TNBC) represents an aggressive subtype of breast cancer that lacks the expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, whose systemic treatment options are currently limited to chemotherapy. Carbon nanoparticles-Fe(II) complex (CNSI-Fe) is a promising antitumor drug that induces ferroptosis to kill tumor cells efficiently. In this study, we combined CNSI-Fe and a ferroptosis inducer sorafenib (SRF) to achieve the efficient chemotherapy of TNBC. CNSI-Fe could adsorb SRF by hydrophobic interaction and π-π stacking with a maximum adsorption capacity of 31 mg/g. During the in vitro assays, CNSI-Fe+SRF combination inhibited the cell viability of 4T1 cells much more efficiently than CNSI-Fe or SRF alone. The high Fe uptake, hydroxyl radical generation and oxidative damages verified the ferroptosis of 4T1 cells upon the CNSI-Fe+SRF treatment. During the in vivo evaluations, SRF enhanced the therapeutic effect of CNSI-Fe as indicated by the higher tumor growth inhibition rate of 67.8 % and the higher survival rate. CNSI captured SRF in tumor to give a 6 mg/kg uptake, which lowered the glutathione peroxidase 4 (GPX4) level and enhanced the hydroxyl radical production of 4T1 tumor. In addition, CNSI-Fe treatment up-regulated the genes associated with antioxidative responses, but the up-regulation was offset by SRF. CNSI-Fe+SRF group showed similar toxicity to mice as SRF alone in the biosafety evaluations. Our results collectively indicated that the combination of CNSI-Fe and SRF could efficiently treat TNBC through ferroptosis.
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Affiliation(s)
- Ping Xie
- Sichuan Enray Pharmaceutical Sciences Company, Chengdu 610095, China
| | - Ting Qu
- Sichuan Enray Pharmaceutical Sciences Company, Chengdu 610095, China
| | - Kexin Tang
- School of Chemistry and Environment, Southwest Minzu University, Chengdu 610041, China
| | - Yuanfang Huang
- Sichuan Enray Pharmaceutical Sciences Company, Chengdu 610095, China
| | - Guangfu Zeng
- Sichuan Enray Pharmaceutical Sciences Company, Chengdu 610095, China
| | - Huahui Yuan
- Sichuan Enray Pharmaceutical Sciences Company, Chengdu 610095, China
| | - Qian Xin
- Sichuan Enray Pharmaceutical Sciences Company, Chengdu 610095, China
| | - Yufeng Zhao
- Sichuan Enray Pharmaceutical Sciences Company, Chengdu 610095, China
| | - Jinmei Yang
- Sichuan Enray Pharmaceutical Sciences Company, Chengdu 610095, China
| | - Cheng Zeng
- Sichuan Enray Pharmaceutical Sciences Company, Chengdu 610095, China
| | - Xian Wu
- School of Chemistry and Environment, Southwest Minzu University, Chengdu 610041, China
| | - Sheng-Tao Yang
- School of Chemistry and Environment, Southwest Minzu University, Chengdu 610041, China.
| | - Xiaohai Tang
- Sichuan Enray Pharmaceutical Sciences Company, Chengdu 610095, China.
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3
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Indelicato E, Delatycki MB, Farmer J, França MC, Perlman S, Rai M, Boesch S. A global perspective on research advances and future challenges in Friedreich ataxia. Nat Rev Neurol 2025; 21:204-215. [PMID: 40032987 DOI: 10.1038/s41582-025-01065-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2025] [Indexed: 03/05/2025]
Abstract
Friedreich ataxia (FRDA) is a rare multisystem, life-limiting disease and is the most common early-onset inherited ataxia in populations of European, Arab and Indian descent. In recent years, substantial progress has been made in dissecting the pathogenesis and natural history of FRDA, and several clinical trials have been initiated. A particularly notable recent achievement was the approval of the nuclear factor erythroid 2-related factor 2 activator omaveloxolone as the first disease-specific therapy for FRDA. In light of these developments, we review milestones in FRDA translational and clinical research over the past 10 years, as well as the various therapeutic strategies currently in the pipeline. We also consider the lessons that have been learned from failed trials and other setbacks. We conclude by presenting a global roadmap for future research, as outlined by the recently established Friedreich's Ataxia Global Clinical Consortium, which covers North and South America, Europe, India, Australia and New Zealand.
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Affiliation(s)
- Elisabetta Indelicato
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Martin B Delatycki
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | | | | | | | - Myriam Rai
- Friedreich's Ataxia Research Alliance, Downingtown, PA, USA
- Laboratory of Experimental Neurology, Brussels, Belgium
| | - Sylvia Boesch
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
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4
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Baile MG, Jones J, Sahr N, Shankar G. Nomlabofusp, a Fusion Protein of Human Frataxin and a Cell Penetrant Peptide, Delivers Mature and Functional Frataxin into Mitochondria. AAPS J 2025; 27:68. [PMID: 40140196 DOI: 10.1208/s12248-025-01054-5] [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: 01/29/2025] [Accepted: 03/06/2025] [Indexed: 03/28/2025] Open
Abstract
Friedreich's ataxia is a rare, progressive, genetic disorder, the root cause of which is a significant deficiency in the mitochondrial protein frataxin. Frataxin is ubiquitously expressed, but its deficiency results in a variety of debilitating symptoms, with disease severity, rate of progression and age of onset inversely correlating with tissue frataxin levels. Nomlabofusp is a novel cell penetrant peptide based recombinant fusion protein designed to enter cells and deliver human FXN into the mitochondria. Using immunofluorescence staining and western blot we show that frataxin delivered by nomlabofusp is detected in the mitochondria of H9c2 and SH-SY5Y cells. Also in these cells, and in C2C12 and HEK293 cells, we demonstrate the presence of mature frataxin after nomlabofusp exposure. Finally, using buccal swab tissue samples taken from study subjects in a Phase 1 clinical trial who received nomlabofusp, we show increases in mature frataxin levels along with marked changes in gene expression post-administration suggesting intracellular pharmacodynamic activity. Together, these results demonstrate that nomlabofusp enters the cell and localizes to the mitochondria, releasing mature frataxin that appears to be biologically active and support the use of nomlabofusp as a potential treatment for patients with Friedreich's ataxia.
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Affiliation(s)
- Matthew G Baile
- Discovery Laboratory, Larimar Therapeutics Inc., King of Prussia, PA, USA
| | - John Jones
- Discovery Laboratory, Larimar Therapeutics Inc., King of Prussia, PA, USA
| | - Natasha Sahr
- Statistics & Quantitative Sciences, Larimar Therapeutics Inc., Bala Cynwyd, PA, USA
| | - Gopi Shankar
- Corporate Office, Larimar Therapeutics Inc., 3 Bala Plaza, Suite 506, Bala Cynwyd, PA, 19004, USA.
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Pandolfo M. Friedreich Ataxia: An (Almost) 30-Year History After Gene Discovery. Neurol Genet 2025; 11:e200236. [PMID: 39810753 PMCID: PMC11731367 DOI: 10.1212/nxg.0000000000200236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 11/26/2024] [Indexed: 01/16/2025]
Abstract
In the late 1800s, Nikolaus Friedreich first described "degenerative atrophy of the posterior columns of the spinal cord," noting its connection to progressive ataxia, sensory loss, and muscle weakness, now recognized as Friedreich ataxia (FRDA). Renewed interest in the disease in the 1970s and 80s by the Quebec Cooperative Group and by Anita Harding led to the development of clinical diagnostic criteria and insights into associated biochemical abnormalities, although the primary defect remained unknown. In 1988, Susan Chamberlain mapped FRDA's location on chromosome 9. In the early 90s, collaborative research, including work by the author's team, identified a gene, later named FXN, containing an expanded GAA repeat-confirming it as the FRDA mutation. This discovery established a diagnostic foundation for FRDA, advancing genetic testing and opening new research avenues. These new areas of study included the characteristics, origin, and pathogenicity of the GAA repeat expansion; the characterization of frataxin, the encoded protein, including its subcellular localization, structure, and function; the identification of cellular pathways disrupted by frataxin deficiency; and the redefinition of FRDA phenotypes based on genetic testing, along with the study of FRDA's natural history. In addition, efforts focused on the search for biomarkers to reflect diagnosis, disease severity, and progression and, most importantly, the identification and development of therapeutic approaches in both preclinical and clinical settings. The creation of cellular and animal models was crucial to this progress, as was the formation of consortia to collaboratively drive basic and clinical research forward. Now, 28 years after the gene discovery, although much remains to be understood about the disease's mechanisms and the development of effective therapies, the progress is undeniable. A thriving community has emerged, uniting researchers, health care providers, industry professionals, individuals with FRDA, their families, and dedicated volunteers. With this collective effort, a cure is within reach.
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Affiliation(s)
- Massimo Pandolfo
- Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
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Beigoli S, Hajizadeh AA, Taghavizadeh Yazdi ME, Zarei H, Vafaee F, Boskabady MH. The brain and systemic oxidative stress and memory changes induced by inhaled paraquat in rat improved by Crocus sativus. Leg Med (Tokyo) 2024; 71:102525. [PMID: 39243568 DOI: 10.1016/j.legalmed.2024.102525] [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: 07/09/2024] [Revised: 08/25/2024] [Accepted: 08/30/2024] [Indexed: 09/09/2024]
Abstract
The present study aimed to investigate the effect of Crocus sativus (Cs) on paraquat (PQ)-induced learning and memory deficits as well as brain and lung oxidative stress and systemic inflammation, and oxidative stress in rats. Rats were exposed to saline (Ctrl) or PQ (PQ groups) aerosols. PQ groups were treated with 0.03 mg/kg/day dexamethasone (Dexa), 20 and 80 mg/kg/day Cs-L and Cs-H, 5 mg/kg/day pioglitazone (Pio), and Cs-L+Pio for 16 days during PQ exposure period. Learning and memory abilities were assessed by Morris water maze (MWM) and passive avoidance tests. PQ group showed increased numbers of total and differential WBCs in blood, and increased malondialdehyde (MDA), in the serum, brain, and lung but reduced thiol, catalase (CAT), and superoxide dismutase (SOD) levels compared to the control group (for all, p < 0.001). The escape latency and traveled distance were increased in the PQ group. However, the time spent in the target quadrant in the MWM test and the latency to enter the dark room were reduced after receiving an electrical shock (p < 0.05 to P<0.001). In all treated groups, measured values were improved compared to PQ group (p < 0.05 to p < 0.001). The combination of Cs-L+Pio showed more pronounced effects compared to either treatment alone (p < 0.05 to p < 0.001). These findings suggest that Cs has neuroprotective properties and may be beneficial in the treatment of neurodegenerative diseases induced by noxious agents such as PQ.
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Affiliation(s)
- Sima Beigoli
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Asghar Hajizadeh
- Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Hossin Zarei
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzaneh Vafaee
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Hossein Boskabady
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Wu L, Huang F, Yang L, Yang L, Sun Z, Zhang J, Xia S, Zhao H, Ding Y, Bian D, Li K. Interplay of FXN expression and lipolysis in white adipocytes plays a critical role in insulin sensitivity in Friedreich's ataxia mouse model. Sci Rep 2024; 14:19876. [PMID: 39191875 DOI: 10.1038/s41598-024-71099-7] [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: 06/12/2024] [Accepted: 08/23/2024] [Indexed: 08/29/2024] Open
Abstract
Frataxin (FXN) is required for iron-sulfur cluster biogenesis, and its loss causes the early-onset neurodegenerative disease Friedreich ataxia (FRDA). Loss of FXN is a susceptibility factor in the development of diabetes, a common metabolic complication after myocardial hypertrophy in patients with FRDA. The underlying mechanism of FXN deficient-induced hyperglycemia in FRDA is, however, poorly understood. In this study, we confirmed that the FXN deficiency mouse model YG8R develops insulin resistance in elder individuals by disturbing lipid metabolic homeostasis in adipose tissues. Evaluation of lipolysis, lipogenesis, and fatty acid β-oxidation showed that lipolysis is most severely affected in white adipose tissues. Consistently, FXN deficiency significantly decreased expression of lipolytic genes encoding adipose triglyceride lipase (Atgl) and hormone-sensitive lipase (Hsl) resulting in adipocyte enlargement and inflammation. Lipolysis induction by fasting or cold exposure remarkably upregulated FXN expression, though FXN deficiency lessened the competency of lipolysis compared with the control or wild type mice. Moreover, we found that the impairment of lipolysis was present at a young age, a few months earlier than hyperglycemia and insulin resistance. Forskolin, an activator of lipolysis, or pioglitazone, an agonist of PPARγ, improved insulin sensitivity in FXN-deficient adipocytes or mice. We uncovered the interplay between FXN expression and lipolysis and found that impairment of lipolysis, particularly the white adipocytes, is an early event, likely, as a primary cause for insulin resistance in FRDA patients at later age.
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Affiliation(s)
- Lin Wu
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Fei Huang
- Endocrinology Department, Yancheng First People's Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng, 224000, People's Republic of China
| | - Lu Yang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Liu Yang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Zichen Sun
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Jinghua Zhang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Siyu Xia
- Endocrinology Department, Yancheng First People's Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng, 224000, People's Republic of China
| | - Hongting Zhao
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Yibing Ding
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Dezhi Bian
- Endocrinology Department, Yancheng First People's Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng, 224000, People's Republic of China.
| | - Kuanyu Li
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China.
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Beigoli S, Hajizadeh AA, Taghavizadeh Yazdi ME, Khosravi R, Vafaee F, Boskabady MH. Improvement of inhaled paraquat induced lung and systemic inflammation, oxidative stress and memory changes by safranal. Toxicon 2024; 241:107687. [PMID: 38484848 DOI: 10.1016/j.toxicon.2024.107687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 03/09/2024] [Accepted: 03/11/2024] [Indexed: 03/19/2024]
Abstract
The effects of safranal and pioglitazone alone and their combination on inhaled paraquat (PQ)-induced systemic oxidative stress and inflammation as well as behavioral changes were examined in rats. In this study, animals were exposed to saline (Ctrl) or PQ (PQ groups) aerosols. PQ exposed animals were treated with dexamethasone, 0.8 and 3.2 mg/kg/day safranal (Saf-L and Saf-H), 5 mg/kg/day pioglitazone (Pio), and Saf-L + Pio for 16 days during PQ exposure period. PQ group showed increased numbers of total and differential WBCs in blood and bronchoalveolar lavage fluid (BALF), increased malondialdehyde (MDA), in the serum BALF and brain reduced thiol, catalase (CAT), and superoxide dismutase (SOD) levels compared to the control group (for all, p < 0.001). The escape latency and traveled distance were enhanced, but the time spent in the target quadrant in the probe day and the latency to enter the dark room 3, 24, 48, and 72 h after receiving an electrical shock, (in the shuttle box test) were decreased in the PQ group (p < 0.05 to P < 0.001). In all treated groups, all measure values were improved compared to PQ group (p < 0.05 to p < 0.001). In combination treated group of Saf-L + Pio, most measured values were more improved than the Saf-L and Pio groups (p < 0.05 to p < 0.001). Saf and Pio improved PQ-induced changes similar to dexamethasone but the effects produced by combination treatments of Saf-L + Pio were more prominent than Pio and Saf-L alone, suggesting a potentiating effect for the combination of the two agents.
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Affiliation(s)
- Sima Beigoli
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Asghar Hajizadeh
- Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Reyhaneh Khosravi
- Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzaneh Vafaee
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Hossein Boskabady
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Qian L, Zhu Y, Deng C, Liang Z, Chen J, Chen Y, Wang X, Liu Y, Tian Y, Yang Y. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases. Signal Transduct Target Ther 2024; 9:50. [PMID: 38424050 PMCID: PMC10904817 DOI: 10.1038/s41392-024-01756-w] [Citation(s) in RCA: 76] [Impact Index Per Article: 76.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 01/13/2024] [Accepted: 01/23/2024] [Indexed: 03/02/2024] Open
Abstract
Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family (PGC-1s), consisting of three members encompassing PGC-1α, PGC-1β, and PGC-1-related coactivator (PRC), was discovered more than a quarter-century ago. PGC-1s are essential coordinators of many vital cellular events, including mitochondrial functions, oxidative stress, endoplasmic reticulum homeostasis, and inflammation. Accumulating evidence has shown that PGC-1s are implicated in many diseases, such as cancers, cardiac diseases and cardiovascular diseases, neurological disorders, kidney diseases, motor system diseases, and metabolic disorders. Examining the upstream modulators and co-activated partners of PGC-1s and identifying critical biological events modulated by downstream effectors of PGC-1s contribute to the presentation of the elaborate network of PGC-1s. Furthermore, discussing the correlation between PGC-1s and diseases as well as summarizing the therapy targeting PGC-1s helps make individualized and precise intervention methods. In this review, we summarize basic knowledge regarding the PGC-1s family as well as the molecular regulatory network, discuss the physio-pathological roles of PGC-1s in human diseases, review the application of PGC-1s, including the diagnostic and prognostic value of PGC-1s and several therapies in pre-clinical studies, and suggest several directions for future investigations. This review presents the immense potential of targeting PGC-1s in the treatment of diseases and hopefully facilitates the promotion of PGC-1s as new therapeutic targets.
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Affiliation(s)
- Lu Qian
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, 710021, China
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China
| | - Yanli Zhu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, 710021, China
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China
| | - Chao Deng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Zhenxing Liang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East, Zhengzhou, 450052, China
| | - Junmin Chen
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, 710021, China
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China
| | - Ying Chen
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Xue Wang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Yanqing Liu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, 710021, China
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China
| | - Ye Tian
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, 710021, China
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China
| | - Yang Yang
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, 710021, China.
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China.
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10
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Lynch DR, Perlman S, Schadt K. Omaveloxolone for the treatment of Friedreich ataxia: clinical trial results and practical considerations. Expert Rev Neurother 2024; 24:251-258. [PMID: 38269532 DOI: 10.1080/14737175.2024.2310617] [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: 09/13/2023] [Accepted: 01/23/2024] [Indexed: 01/26/2024]
Abstract
INTRODUCTION Omavaloxolone, an NRF2 activator, recently became the first drug approved specifically for the treatment of Friedreich ataxia (FRDA). This landmark achievement provides a background for a review of the detailed data leading to the approval. AREAS COVERED The authors review the data from the 4 major articles on FRDA in the context of the authors' considerable (>1000 patients) experience in treating individuals with FRDA. The data is presented in the context not only of its scientific meaning but also in the practical context of therapy in FRDA. EXPERT OPINION Omaveloxolone provides a significant advance in the treatment of FRDA that is likely to be beneficial in a majority of the FRDA population. The data suggesting a benefit is consistent, and adverse issues are relatively modest. The major remaining questions are the subgroups that are most responsive and how long the beneficial effects will remain significant in FRDA patients.
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Affiliation(s)
- David R Lynch
- Friedrech Ataxia Program, Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Susan Perlman
- Department of Neurology, David Geffen UCLA School of Medicine, Los Angeles, CA, USA
| | - Kim Schadt
- Friedreich Ataxia Program, Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
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11
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Edzeamey FJ, Ramchunder Z, Pourzand C, Anjomani Virmouni S. Emerging antioxidant therapies in Friedreich's ataxia. Front Pharmacol 2024; 15:1359618. [PMID: 38379897 PMCID: PMC10876797 DOI: 10.3389/fphar.2024.1359618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 01/25/2024] [Indexed: 02/22/2024] Open
Abstract
Friedreich's ataxia (FRDA) is a rare childhood neurologic disorder, affecting 1 in 50,000 Caucasians. The disease is caused by the abnormal expansion of the GAA repeat sequence in intron 1 of the FXN gene, leading to the reduced expression of the mitochondrial protein frataxin. The disease is characterised by progressive neurodegeneration, hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities. The reduced expression of frataxin has been suggested to result in the downregulation of endogenous antioxidant defence mechanisms and mitochondrial bioenergetics, and the increase in mitochondrial iron accumulation thereby leading to oxidative stress. The confirmation of oxidative stress as one of the pathological signatures of FRDA led to the search for antioxidants which can be used as therapeutic modality. Based on this observation, antioxidants with different mechanisms of action have been explored for FRDA therapy since the last two decades. In this review, we bring forth all antioxidants which have been investigated for FRDA therapy and have been signed off for clinical trials. We summarise their various target points in FRDA disease pathway, their performances during clinical trials and possible factors which might have accounted for their failure or otherwise during clinical trials. We also discuss the limitation of the studies completed and propose possible strategies for combinatorial therapy of antioxidants to generate synergistic effect in FRDA patients.
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Affiliation(s)
- Fred Jonathan Edzeamey
- Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health, Medicine, and Life Sciences (CHMLS), Brunel University London, Uxbridge, United Kingdom
| | - Zenouska Ramchunder
- Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health, Medicine, and Life Sciences (CHMLS), Brunel University London, Uxbridge, United Kingdom
| | - Charareh Pourzand
- Department of Life Sciences, University of Bath, Bath, United Kingdom
- Centre for Therapeutic Innovation, University of Bath, Bath, United Kingdom
| | - Sara Anjomani Virmouni
- Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health, Medicine, and Life Sciences (CHMLS), Brunel University London, Uxbridge, United Kingdom
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Saini AK, Anil N, Vijay AN, Mangla B, Javed S, Kumar P, Ahsan W. Recent Advances in the Treatment Strategies of Friedreich's Ataxia: A Review of Potential Drug Candidates and their Underlying Mechanisms. Curr Pharm Des 2024; 30:1472-1489. [PMID: 38638052 DOI: 10.2174/0113816128288707240404051856] [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: 11/22/2023] [Accepted: 03/21/2024] [Indexed: 04/20/2024]
Abstract
BACKGROUND Friedreich's Ataxia (FRDA) is a rare hereditary neurodegenerative disorder characterized by progressive ataxia, cardiomyopathy, and diabetes. The disease is caused by a deficiency of frataxin, a mitochondrial protein involved in iron-sulfur cluster synthesis and iron metabolism. OBJECTIVE This review aims to summarize recent advances in the development of treatment strategies for FRDA, with a focus on potential drug candidates and their mechanisms of action. METHODS A comprehensive literature search was conducted using various authentic scientific databases to identify studies published in the last decade that investigated potential treatment strategies for FRDA. The search terms used included "Friedreich's ataxia", "treatment", "drug candidates", and "mechanisms of action". RESULTS To date, only one drug got approval from US-FDA in the year 2023; however, significant developments were achieved in FRDA-related research focusing on diverse therapeutic interventions that could potentially alleviate the symptoms of this disease. Several promising drug candidates have been identified for the treatment of FRDA, which target various aspects of frataxin deficiency and aim to restore frataxin levels, reduce oxidative stress, and improve mitochondrial function. Clinical trials have shown varying degrees of success, with some drugs demonstrating significant improvements in neurological function and quality of life in FRDA patients. CONCLUSION While there has been significant progress in the development of treatment strategies for FRDA, further research is needed to optimize these approaches and identify the most effective and safe treatment options for patients. The integration of multiple therapeutic strategies may be necessary to achieve the best outcomes in FRDA management.
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Affiliation(s)
- Aman Kumar Saini
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi 110017, India
| | - Neha Anil
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi 110017, India
| | - Ardra N Vijay
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi 110017, India
| | - Bharti Mangla
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi 110017, India
| | - Shamama Javed
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan, P. Box No. 114, Saudi Arabia
| | - Pankaj Kumar
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi 110017, India
| | - Waquar Ahsan
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University, Jazan, P. Box No. 114, Saudi Arabia
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13
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Yalçın T, Kaya S, Kuloğlu T, Yiğin A. N-Acetylcysteine May Regulate Altered Meteorin-Like Levels in Testicular Tissue due to Aluminum Exposure. Biol Trace Elem Res 2023; 201:5335-5345. [PMID: 37016183 DOI: 10.1007/s12011-023-03656-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 03/30/2023] [Indexed: 04/06/2023]
Abstract
Aluminum (AL) is a heavy metal known to have toxic effects on the reproductive system. It is known that N-acetylcysteine (NAC), which has an antioxidant effect, is a useful chelator for heavy metals. This study aimed to determine whether NAC may reduce AL-induced oxidative stress, inflammation, and germ cell apoptosis in testicular tissues and its effects on meteorin-like (METRNL) levels, which are known to play a role in energy metabolism. In this experimental study, 28 Sprague-Dawley male rats were randomly divided into 4 groups (n = 7): control, AL (30 mg/kg/day AL), AL + NAC (30 mg/kg/day AL + 150 mg/kg/day NAC), and NAC (150 mg/kg/day NAC). All AL and NAC applications were performed intraperitoneally for 14 days. At the end of the experiment, the effects of AL and/or NAC applications on testicular tissue were examined histomorphometrically, histopathologically, immunohistochemically, and biochemically. It was determined that AL exposure caused histomorphometric and histopathological changes, oxidative stress, apoptosis of germ cells, and inflammation in testicular tissues. In addition, AL caused an increase in METRNL levels. It was determined that NAC treatment significantly reduced the negative effects of AL. NAC therapy may be a protective strategy in reproductive toxicity due to AL exposure.
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Affiliation(s)
- Tuba Yalçın
- Vocational Higher School of Healthcare Studies, Batman University, Batman, Turkey
| | - Sercan Kaya
- Vocational Higher School of Healthcare Studies, Batman University, Batman, Turkey.
| | - Tuncay Kuloğlu
- Department of Histology and Embryology, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Akın Yiğin
- Department of Genetics, Faculty of Veterinary Medicine, Harran University, Sanliurfa, Turkey
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14
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Turchi R, Sciarretta F, Ceci V, Tiberi M, Audano M, Pedretti S, Panebianco C, Nesci V, Pazienza V, Ferri A, Carotti S, Chiurchiù V, Mitro N, Lettieri-Barbato D, Aquilano K. Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich's ataxia mouse model. iScience 2023; 26:107713. [PMID: 37701569 PMCID: PMC10494209 DOI: 10.1016/j.isci.2023.107713] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 08/02/2023] [Accepted: 08/23/2023] [Indexed: 09/14/2023] Open
Abstract
Friedreich's ataxia (FA) is a neurodegenerative disease resulting from a mutation in the FXN gene, leading to mitochondrial frataxin deficiency. FA patients exhibit increased visceral adiposity, inflammation, and heightened diabetes risk, negatively affecting prognosis. We investigated visceral white adipose tissue (vWAT) in a murine model (KIKO) to understand its role in FA-related metabolic complications. RNA-seq analysis revealed altered expression of inflammation, angiogenesis, and fibrosis genes. Diabetes-like traits, including larger adipocytes, immune cell infiltration, and increased lactate production, were observed in vWAT. FXN downregulation in cultured adipocytes mirrored vWAT diabetes-like features, showing metabolic shifts toward glycolysis and lactate production. Metagenomic analysis indicated a reduction in fecal butyrate-producing bacteria, known to exert antidiabetic effects. A butyrate-enriched diet restrained vWAT abnormalities and mitigated diabetes features in KIKO mice. Our work emphasizes the role of vWAT in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management.
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Affiliation(s)
- Riccardo Turchi
- Department Biology, University of Rome Tor Vergata, Rome, Italy
| | | | - Veronica Ceci
- PhD Program in Evolutionary Biology and Ecology, Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Marta Tiberi
- Laboratory of Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Matteo Audano
- DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Silvia Pedretti
- DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Concetta Panebianco
- Gastroenterology Unit Fondazione IRCSS “Casa Sollievo della Sofferenza” Hospital San Giovanni Rotondo (FG)-Italy
| | - Valentina Nesci
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Division of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Valerio Pazienza
- Gastroenterology Unit Fondazione IRCSS “Casa Sollievo della Sofferenza” Hospital San Giovanni Rotondo (FG)-Italy
| | - Alberto Ferri
- Division of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, Rome, Italy
- Institute of Traslational Pharmacology, IFT-CNR, Rome, Italy
| | - Simone Carotti
- Microscopic and Ultrastructural Anatomy Research Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
- Predictive Molecular Diagnostics, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Valerio Chiurchiù
- Laboratory of Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Rome, Italy
- Institute of Traslational Pharmacology, IFT-CNR, Rome, Italy
| | - Nico Mitro
- DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Daniele Lettieri-Barbato
- Department Biology, University of Rome Tor Vergata, Rome, Italy
- IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Katia Aquilano
- Department Biology, University of Rome Tor Vergata, Rome, Italy
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15
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Luffarelli R, Panarello L, Quatrana A, Tiano F, Fortuni S, Rufini A, Malisan F, Testi R, Condò I. Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich's Ataxia Cells. Int J Mol Sci 2023; 24:12687. [PMID: 37628866 PMCID: PMC10454386 DOI: 10.3390/ijms241612687] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/27/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Friedreich's ataxia (FRDA) is a rare monogenic disease characterized by multisystem, slowly progressive degeneration. Because of the genetic defect in a non-coding region of FXN gene, FRDA cells exhibit severe deficit of frataxin protein levels. Hence, FRDA pathophysiology is characterized by a plethora of metabolic disruptions related to iron metabolism, mitochondrial homeostasis and oxidative stress. Importantly, an impairment of the antioxidant defences exacerbates the oxidative damage. This appears closely associated with the disablement of key antioxidant proteins, such as the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and the mitochondrial superoxide dismutase (MnSOD). The cytokine interferon gamma (IFN-γ) has been shown to increase frataxin expression in FRDA cells and to improve functional deficits in FRDA mice. Currently, IFN-γ represents a potential therapy under clinical evaluation in FRDA patients. Here, we show that IFN-γ induces a rapid expression of Nrf2 and MnSOD in different cell types, including FRDA patient-derived fibroblasts. Our data indicate that IFN-γ signals two separate pathways to enhance Nrf2 and MnSOD levels in FRDA fibroblasts. MnSOD expression increased through an early transcriptional regulation, whereas the levels of Nrf2 are induced by a post-transcriptional mechanism. We demonstrate that the treatment of FRDA fibroblasts with IFN-γ stimulates a non-canonical Nrf2 activation pathway through p21 and potentiates antioxidant responses under exposure to hydrogen peroxide. Moreover, IFN-γ significantly reduced the sensitivity to hydrogen peroxide-induced cell death in FRDA fibroblasts. Collectively, these results indicate the presence of multiple pathways triggered by IFN-γ with therapeutic relevance to FRDA.
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Affiliation(s)
- Riccardo Luffarelli
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; (R.L.); (L.P.); (A.Q.); (F.T.); (S.F.); (A.R.); (F.M.); (R.T.)
| | - Luca Panarello
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; (R.L.); (L.P.); (A.Q.); (F.T.); (S.F.); (A.R.); (F.M.); (R.T.)
| | - Andrea Quatrana
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; (R.L.); (L.P.); (A.Q.); (F.T.); (S.F.); (A.R.); (F.M.); (R.T.)
| | - Francesca Tiano
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; (R.L.); (L.P.); (A.Q.); (F.T.); (S.F.); (A.R.); (F.M.); (R.T.)
| | - Silvia Fortuni
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; (R.L.); (L.P.); (A.Q.); (F.T.); (S.F.); (A.R.); (F.M.); (R.T.)
| | - Alessandra Rufini
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; (R.L.); (L.P.); (A.Q.); (F.T.); (S.F.); (A.R.); (F.M.); (R.T.)
- Departmental Faculty of Medicine and Surgery, Saint Camillus International University of Health and Medical Sciences, 00131 Rome, Italy
| | - Florence Malisan
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; (R.L.); (L.P.); (A.Q.); (F.T.); (S.F.); (A.R.); (F.M.); (R.T.)
| | - Roberto Testi
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; (R.L.); (L.P.); (A.Q.); (F.T.); (S.F.); (A.R.); (F.M.); (R.T.)
| | - Ivano Condò
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; (R.L.); (L.P.); (A.Q.); (F.T.); (S.F.); (A.R.); (F.M.); (R.T.)
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16
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Lew SY, Mohd Hisam NS, Phang MWL, Syed Abdul Rahman SN, Poh RYY, Lim SH, Kamaruzzaman MA, Chau SC, Tsui KC, Lim LW, Wong KH. Adenosine Improves Mitochondrial Function and Biogenesis in Friedreich's Ataxia Fibroblasts Following L-Buthionine Sulfoximine-Induced Oxidative Stress. BIOLOGY 2023; 12:biology12040559. [PMID: 37106759 PMCID: PMC10136261 DOI: 10.3390/biology12040559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/25/2023] [Accepted: 03/30/2023] [Indexed: 04/29/2023]
Abstract
Adenosine is a nucleoside that is widely distributed in the central nervous system and acts as a central excitatory and inhibitory neurotransmitter in the brain. The protective role of adenosine in different pathological conditions and neurodegenerative diseases is mainly mediated by adenosine receptors. However, its potential role in mitigating the deleterious effects of oxidative stress in Friedreich's ataxia (FRDA) remains poorly understood. We aimed to investigate the protective effects of adenosine against mitochondrial dysfunction and impaired mitochondrial biogenesis in L-buthionine sulfoximine (BSO)-induced oxidative stress in dermal fibroblasts derived from an FRDA patient. The FRDA fibroblasts were pre-treated with adenosine for 2 h, followed by 12.50 mM BSO to induce oxidative stress. Cells in medium without any treatments or pre-treated with 5 µM idebenone served as the negative and positive controls, respectively. Cell viability, mitochondrial membrane potential (MMP), aconitase activity, adenosine triphosphate (ATP) level, mitochondrial biogenesis, and associated gene expressions were assessed. We observed disruption of mitochondrial function and biogenesis and alteration in gene expression patterns in BSO-treated FRDA fibroblasts. Pre-treatment with adenosine ranging from 0-600 µM restored MMP, promoted ATP production and mitochondrial biogenesis, and modulated the expression of key metabolic genes, namely nuclear respiratory factor 1 (NRF1), transcription factor A, mitochondrial (TFAM), and NFE2-like bZIP transcription factor 2 (NFE2L2). Our study demonstrated that adenosine targeted mitochondrial defects in FRDA, contributing to improved mitochondrial function and biogenesis, leading to cellular iron homeostasis. Therefore, we suggest a possible therapeutic role for adenosine in FRDA.
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Affiliation(s)
- Sze Yuen Lew
- Department of Anatomy, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | | | - Michael Weng Lok Phang
- Department of Anatomy, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | | | - Rozaida Yuen Ying Poh
- Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Siew Huah Lim
- Department of Chemistry, Faculty of Science, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Mohd Amir Kamaruzzaman
- Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Cheras, Kuala Lumpur 56000, Malaysia
| | - Sze Chun Chau
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Ka Chun Tsui
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Lee Wei Lim
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Kah Hui Wong
- Department of Anatomy, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
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17
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Wan H, Yan YD, Hu XM, Shang L, Chen YH, Huang YX, Zhang Q, Yan WT, Xiong K. Inhibition of mitochondrial VDAC1 oligomerization alleviates apoptosis and necroptosis of retinal neurons following OGD/R injury. Ann Anat 2023; 247:152049. [PMID: 36690044 DOI: 10.1016/j.aanat.2023.152049] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/28/2022] [Accepted: 01/03/2023] [Indexed: 01/21/2023]
Abstract
Ischemia-reperfusion (I/R) injury is a common pathological mechanism in many retinal diseases, which can lead to cell death via mitochondrial dysfunction. Voltage-dependent anion channel 1 (VDAC1), which is mainly located in the outer mitochondrial membrane, is the gatekeeper of mitochondria. The permeability of mitochondrial membrane can be regulated by controlling the oligomerization of VDAC1. However, the functional mechanism of VDAC1 in retinal I/R injury was unclear. Our results demonstrate that oxygen-glucose deprivation and re-oxygenation (OGD/R) injury leads to apoptosis, necroptosis, and mitochondrial dysfunction of R28 cells. The OGD/R injury increases the levels of VDAC1 oligomerization. Inhibition of VDAC1 oligomerization by VBIT-12 rescued mitochondrial dysfunction by OGD/R and also reduced apoptosis/necroptosis of R28 cells. In vivo, the use of VBIT-12 significantly reduced aHIOP-induced neuronal death (apoptosis/necroptosis) in the rat retina. Our findings indicate that VDAC1 oligomers may open and enlarge mitochondrial membrane pores during OGD/R injury, leading to the release of death-related factors in mitochondria, resulting in apoptosis and necroptosis. This study provides a potential therapeutic strategy against ocular diseases caused by I/R injury.
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Affiliation(s)
- Hao Wan
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, China
| | - Yan-di Yan
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xi-Min Hu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Lei Shang
- Jiangxi Research Institute of Ophthalmology and Visual Sciences, Affiliated Eye Hospital of Nanchang University, Nanchang 330006, China
| | - Yu-Hua Chen
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, China
| | - Yan-Xia Huang
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, China
| | - Qi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, China
| | - Wei-Tao Yan
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, China.
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, China; Hunan Key Laboratory of Ophthalmology, Changsha 410008, China; Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou 571199, China.
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18
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Seminotti B, Grings M, Glänzel NM, Vockley J, Leipnitz G. Peroxisome proliferator-activated receptor (PPAR) agonists as a potential therapy for inherited metabolic disorders. Biochem Pharmacol 2023; 209:115433. [PMID: 36709926 DOI: 10.1016/j.bcp.2023.115433] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 01/27/2023]
Abstract
Inherited metabolic disorders (IMDs) are genetic disorders that cause a disruption of a specific metabolic pathway leading to biochemical, clinical and pathophysiological sequelae. While the metabolite abnormalities in body fluids and tissues can usually be defined by directed or broad-spectrum metabolomic analysis, the pathophysiology of these changes is often not obvious. Mounting evidence has revealed that secondary mitochondrial dysfunction, mainly oxidative phosphorylation impairment and elevated reactive oxygen species, plays a pivotal role in many disorders. Peroxisomal proliferator-activated receptors (PPARs) consist of a group of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ) that regulate multiple cellular functions and processes, including response to oxidative stress, inflammation, lipid metabolism, and mitochondrial bioenergetics and biogenesis. In this context, the activation of PPARs has been shown to stimulate oxidative phosphorylation and reduce reactive species levels. Thus, pharmacological treatment with PPAR activators, such as fibrates, has gained much attention in the last 15 years. This review summarizes preclinical (animal models and patient-derived cells) and clinical data on the effect of PPARs in IMDs.
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Affiliation(s)
- Bianca Seminotti
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mateus Grings
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil
| | - Nícolas Manzke Glänzel
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil
| | - Jerry Vockley
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Guilhian Leipnitz
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite, 500, CEP 90035-190, Porto Alegre, RS, Brazil; Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
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Pizcueta P, Vergara C, Emanuele M, Vilalta A, Rodríguez-Pascau L, Martinell M. Development of PPARγ Agonists for the Treatment of Neuroinflammatory and Neurodegenerative Diseases: Leriglitazone as a Promising Candidate. Int J Mol Sci 2023; 24:ijms24043201. [PMID: 36834611 PMCID: PMC9961553 DOI: 10.3390/ijms24043201] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/21/2023] [Accepted: 02/01/2023] [Indexed: 02/08/2023] Open
Abstract
Increasing evidence suggests that the peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, plays an important role in physiological processes in the central nervous system (CNS) and is involved in cellular metabolism and repair. Cellular damage caused by acute brain injury and long-term neurodegenerative disorders is associated with alterations of these metabolic processes leading to mitochondrial dysfunction, oxidative stress, and neuroinflammation. PPARγ agonists have demonstrated the potential to be effective treatments for CNS diseases in preclinical models, but to date, most drugs have failed to show efficacy in clinical trials of neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. The most likely explanation for this lack of efficacy is the insufficient brain exposure of these PPARγ agonists. Leriglitazone is a novel, blood-brain barrier (BBB)-penetrant PPARγ agonist that is being developed to treat CNS diseases. Here, we review the main roles of PPARγ in physiology and pathophysiology in the CNS, describe the mechanism of action of PPARγ agonists, and discuss the evidence supporting the use of leriglitazone to treat CNS diseases.
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Affiliation(s)
- Pilar Pizcueta
- Minoryx Therapeutics SL, 08302 Barcelona, Spain
- Correspondence:
| | | | - Marco Emanuele
- Minoryx Therapeutics BE, Gosselies, 6041 Charleroi, Belgium
| | | | | | - Marc Martinell
- Minoryx Therapeutics SL, 08302 Barcelona, Spain
- Minoryx Therapeutics BE, Gosselies, 6041 Charleroi, Belgium
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Pandolfo M, Reetz K, Darling A, Rodriguez de Rivera FJ, Henry PG, Joers J, Lenglet C, Adanyeguh I, Deelchand D, Mochel F, Pousset F, Pascual S, Van den Eede D, Martin-Ugarte I, Vilà-Brau A, Mantilla A, Pascual M, Martinell M, Meya U, Durr A. Efficacy and Safety of Leriglitazone in Patients With Friedreich Ataxia. Neurol Genet 2022; 8:e200034. [DOI: 10.1212/nxg.0000000000200034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 08/18/2022] [Indexed: 11/06/2022]
Abstract
Background and ObjectivesFriedreich ataxia (FRDA) is an autosomal recessive ataxia with no approved treatments. Leriglitazone is a selective peroxisome proliferator–activated receptor γ agonist that crosses the blood-brain barrier and, in preclinical models, improved mitochondrial function and energy production. We assessed effects of leriglitazone in patients with FRDA in a proof-of-concept study.MethodsIn this double-blind, randomized controlled trial, eligible participants (age 12–60 years) had genetically confirmed FRDA, a Scale for the Assessment and Rating of Ataxia (SARA) total score <25, and a SARA item 1 score of 2–6, inclusive. Key exclusion criteria were age at FRDA onset ≥25 years and history of cardiac dysfunction. Participants were randomly assigned (2:1) to receive a daily, oral, individualized dose of leriglitazone or placebo for 48 weeks. The primary endpoint was the change from baseline to week 48 in spinal cord area (C2-C3) (measured by MRI). Secondary endpoints included the change from baseline to week 48 in iron accumulation in the dentate nucleus (quantitative susceptibility mapping) and totalN-acetylaspartate to myo-inositol (tNAA/mIns) ratio.ResultsOverall, 39 patients were enrolled (mean age 24 years; 43.6% women; mean time since symptom onset 10.5 years): 26 patients received leriglitazone (20 completed) and 13 received placebo (12 completed). There was no difference between groups in spinal cord area from baseline to week 48 (least-squares [LS] mean change [standard error (SE)]: leriglitazone, −0.39 [0.55] mm2; placebo, 0.08 [0.72] mm2;p= 0.61). Iron accumulation in the dentate nucleus was greater with placebo (LS mean change [SE]: leriglitazone, 0.10 [1.33] ppb; placebo, 4.86 [1.84] ppb;p= 0.05), and a numerical difference was seen in tNAA/mIns ratio (LS mean change [SE]: leriglitazone, 0.03 [0.02]; placebo, −0.02 [0.03];p= 0.25). The most frequent adverse event was peripheral edema (leriglitazone 73.1%, placebo 0%).DiscussionThe primary endpoint of change in spinal cord area was not met. Secondary endpoints provide evidence supporting proof of concept for leriglitazone mode of action and, with acceptable safety data, support larger studies in patients with FRDA.Trial Registration InformationClinicalTrials.gov:NCT03917225; EudraCT: 2018-004405-64; submitted April 17, 2019; first patient enrolled April 2, 2019.clinicaltrials.gov/ct2/show/NCT03917225?term=NCT03917225&draw=2&rank=1.Classification of EvidenceThis study provides Class I evidence that individualized dosing of leriglitazone, compared with placebo, is not associated with changes in spinal cord area in patients with FRDA.
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Aggarwal R, Potel KN, McFalls EO, Butterick TA, Kelly RF. Novel Therapeutic Approaches Enhance PGC1-alpha to Reduce Oxidant Stress-Inflammatory Signaling and Improve Functional Recovery in Hibernating Myocardium. Antioxidants (Basel) 2022; 11:2155. [PMID: 36358527 PMCID: PMC9686496 DOI: 10.3390/antiox11112155] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 10/29/2022] [Accepted: 10/30/2022] [Indexed: 09/02/2023] Open
Abstract
Ischemic heart disease affects millions of people around the world. Current treatment options, including coronary artery bypass grafting, do not result in full functional recovery, highlighting the need for novel adjunctive therapeutic approaches. Hibernation describes the myocardial response to prolonged ischemia and involves a set of complex cytoprotective metabolic and functional adaptations. PGC1-alpha, a key regulator of mitochondrial energy metabolism and inhibitor of oxidant-stress-inflammatory signaling, is known to be downregulated in hibernating myocardium. PGC1-alpha is a critical component of cellular stress responses and links cellular metabolism with inflammation in the ischemic heart. While beneficial in the acute setting, a chronic state of hibernation can be associated with self-perpetuating oxidant stress-inflammatory signaling which leads to tissue injury. It is likely that incomplete functional recovery following revascularization of chronically ischemic myocardium is due to persistence of metabolic changes as well as prooxidant and proinflammatory signaling. Enhancement of PGC1-alpha signaling has been proposed as a possible way to improve functional recovery in patients with ischemic heart disease. Adjunctive mesenchymal stem cell therapy has been shown to induce PGC1-alpha signaling in hibernating myocardium and could help improve clinical outcomes for patients undergoing bypass surgery.
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Affiliation(s)
- Rishav Aggarwal
- Division of Cardiothoracic Surgery, Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Koray N. Potel
- School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - Edward O. McFalls
- Division of Cardiology, Richmond VA Medical Center, Richmond, VA 23249-4915, USA
| | - Tammy A. Butterick
- Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Research, Center for Veterans Research and Education, Minneapolis, MN 55417, USA
| | - Rosemary F. Kelly
- Division of Cardiothoracic Surgery, Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA
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22
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She Y, Yu M, Wang L, Wang Y, Fang P, Zhang Z. Emerging Protective Actions of PGC-1 α in Diabetic Nephropathy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6580195. [PMID: 36262282 PMCID: PMC9576408 DOI: 10.1155/2022/6580195] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/14/2022] [Accepted: 09/26/2022] [Indexed: 11/23/2022]
Abstract
Renal impairment is affected by various mechanisms of oxidative stress, mitochondrial dysfunction, and basement membrane thickening, which are the major causes of renal dysfunction in diabetes. Of note, hyperglycemia-induced mitochondrial dysfunction has been identified as a common cause of diabetic nephropathy and renal impairment, and the decrease in PGC-1α expression brought on by hyperglycemia plays an immensurable role in both the reduction of mitochondrial biogenesis and the rise in oxidative stress. Reduced PGC-1α expression levels may occur with rising SGLT2-dependent increase of cytoplasmic sodium and protons in the renal cells of diabetes, even if the precise mechanism of hyperglycemia-induced disruption of PGC-1α expression has not been identified. Additionally, it has been observed that SGLT2 inhibitors enhance PGC-1α expression and activity and decrease cytoplasmic sodium and protons in many kidney cells, which may be helpful in reducing renal impairment brought on by diabetes. This review summarizes our and other recent studies on the function of PGC-1α in diabetic nephropathy, provides another potential mediator of the lower PGC-1α expression levels brought on by hyperglycemia in diabetics, and identifies a new pathogenesis of diabetes-related renal impairment. It also explains the mechanism underlying the protective effects of SGLT2 inhibitors on diabetic nephropathy. Therefore, it should be taken into account that SGLT2 inhibitors are an effective therapeutic strategy for reducing renal dysfunction caused by diabetes.
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Affiliation(s)
- Yuqing She
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
- Department of Endocrinology, Pukou Branch of Jiangsu People's Hospital, Nanjing 211899, China
| | - Mei Yu
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Liang Wang
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yajing Wang
- Department of Endocrinology, Clinical Medical College, Yangzhou University, Yangzhou 225001, China
| | - Penghua Fang
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zhenwen Zhang
- Department of Endocrinology, Clinical Medical College, Yangzhou University, Yangzhou 225001, China
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An open-label pilot study of recombinant granulocyte-colony stimulating factor in Friedreich's ataxia. Nat Commun 2022; 13:4655. [PMID: 35945193 PMCID: PMC9363409 DOI: 10.1038/s41467-022-31450-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 06/20/2022] [Indexed: 11/25/2022] Open
Abstract
Friedreich's ataxia (FA) is an inherited progressive neurodegenerative disease for which there is no proven disease-modifying treatment. Here we perform an open-label, pilot study of recombinant human granulocyte-colony stimulating factor (G-CSF) administration in seven people with FA (EudraCT: 2017-003084-34); each participant receiving a single course of G-CSF (Lenograstim; 1.28 million units per kg per day for 5 days). The primary outcome is peripheral blood mononuclear cell frataxin levels over a 19-day period. The secondary outcomes include safety, haematopoietic stem cell (HSC) mobilisation, antioxidant levels and mitochondrial enzyme activity. The trial meets pre-specified endpoints. We show that administration of G-CSF to people with FA is safe. Mobilisation of HSCs in response to G-CSF is comparable to that of healthy individuals. Notably, sustained increases in cellular frataxin concentrations and raised PGC-1α and Nrf2 expression are detected. Our findings show potential for G-CSF therapy to have a clinical impact in people with FA.
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Abeti R, Jasoliya M, Al-Mahdawi S, Pook M, Gonzalez-Robles C, Hui CK, Cortopassi G, Giunti P. A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models. Front Mol Biosci 2022; 9:830650. [PMID: 35664670 PMCID: PMC9160322 DOI: 10.3389/fmolb.2022.830650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 03/17/2022] [Indexed: 11/22/2022] Open
Abstract
Friedreich’s ataxia (FA) is an inherited multisystemic neuro- and cardio-degenerative disorder. Seventy-four clinical trials are listed for FA (including past and present), but none are considered FDA/EMA-approved therapy. To date, FA therapeutic strategies have focused along two main lines using a single-drug approach: a) increasing frataxin and b) enhancing downstream pathways, including antioxidant levels and mitochondrial function. Our novel strategy employed a combinatorial approach to screen approved compounds to determine if a combination of molecules provided an additive or synergistic benefit to FA cells and/or animal models. Eight single drug molecules were administered to FA fibroblast patient cells: nicotinamide riboside, hemin, betamethasone, resveratrol, epicatechin, histone deacetylase inhibitor 109, methylene blue, and dimethyl fumarate. We measured their individual ability to induce FXN transcription and mitochondrial biogenesis in patient cells. Single-drug testing highlighted that dimethyl fumarate and resveratrol increased these two parameters. In addition, the simultaneous administration of these two drugs was the most effective in terms of FXN mRNA and mitobiogenesis increase. Interestingly, this combination also improved mitochondrial functions and reduced reactive oxygen species in neurons and cardiomyocytes. Behavioral tests in an FA mouse model treated with dimethyl fumarate and resveratrol demonstrated improved rotarod performance. Our data suggest that dimethyl fumarate is effective as a single agent, and the addition of resveratrol provides further benefit in some assays without showing toxicity. Therefore, they could be a valuable combination to counteract FA pathophysiology. Further studies will help fully understand the potential of a combined therapeutic strategy in FA pathophysiology.
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Affiliation(s)
- Rosella Abeti
- Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL, Institute of Neurology, London, United Kingdom
- *Correspondence: Rosella Abeti, ; Paola Giunti,
| | - Mittal Jasoliya
- Department of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, CA, United States
| | - Sahar Al-Mahdawi
- Department of Life Sciences, Institute of Environment, Health, and Societies, College of Health and Life Sciences, Division of Biosciences, Brunel University London, Uxbridge, United Kingdom
| | - Mark Pook
- Department of Life Sciences, Institute of Environment, Health, and Societies, College of Health and Life Sciences, Division of Biosciences, Brunel University London, Uxbridge, United Kingdom
| | - Cristina Gonzalez-Robles
- Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL, Institute of Neurology, London, United Kingdom
| | - Chun Kiu Hui
- Department of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, CA, United States
| | - Gino Cortopassi
- Department of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, CA, United States
| | - Paola Giunti
- Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL, Institute of Neurology, London, United Kingdom
- *Correspondence: Rosella Abeti, ; Paola Giunti,
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25
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Durai P, Beeraka NM, Ramachandrappa HVP, Krishnan P, Gudur P, Raghavendra NM, Ravanappa PKB. Advances in PPARs Molecular Dynamics and Glitazones as a Repurposing Therapeutic Strategy through Mitochondrial Redox Dynamics against Neurodegeneration. Curr Neuropharmacol 2022; 20:893-915. [PMID: 34751120 PMCID: PMC9881103 DOI: 10.2174/1570159x19666211109141330] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/20/2021] [Accepted: 09/17/2021] [Indexed: 11/22/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) activity has significant implications for the development of novel therapeutic modalities against neurodegenerative diseases. Although PPAR-α, PPAR-β/δ, and PPAR-γ nuclear receptor expressions are significantly reported in the brain, their implications in brain physiology and other neurodegenerative diseases still require extensive studies. PPAR signaling can modulate various cell signaling mechanisms involved in the cells contributing to on- and off-target actions selectively to promote therapeutic effects as well as the adverse effects of PPAR ligands. Both natural and synthetic ligands for the PPARα, PPARγ, and PPARβ/δ have been reported. PPARα (WY 14.643) and PPARγ agonists can confer neuroprotection by modulating mitochondrial dynamics through the redox system. The pharmacological effect of these agonists may deliver effective clinical responses by protecting vulnerable neurons from Aβ toxicity in Alzheimer's disease (AD) patients. Therefore, the current review delineated the ligands' interaction with 3D-PPARs to modulate neuroprotection, and also deciphered the efficacy of numerous drugs, viz. Aβ aggregation inhibitors, vaccines, and γ-secretase inhibitors against AD; this review elucidated the role of PPAR and their receptor isoforms in neural systems, and neurodegeneration in human beings. Further, we have substantially discussed the efficacy of PPREs as potent transcription factors in the brain, and the role of PPAR agonists in neurotransmission, PPAR gamma coactivator-1α (PGC-1α) and mitochondrial dynamics in neuroprotection during AD conditions. This review concludes with the statement that the development of novel PPARs agonists may benefit patients with neurodegeneration, mainly AD patients, which may help mitigate the pathophysiology of dementia, subsequently improving overall the patient's quality of life.
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Affiliation(s)
- Priya Durai
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru 570 015, India and JSS Academy of Higher Education & Research, Mysuru, Karnataka, India
| | - Narasimha M. Beeraka
- Center of Excellence in Regenerative Medicine and Molecular Biology (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru 570 015, Karnataka, India;,I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119146, Russia
| | - Hemanth Vikram Poola Ramachandrappa
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru 570 015, India and JSS Academy of Higher Education & Research, Mysuru, Karnataka, India
| | | | - Pranesh Gudur
- Swamy Vivekananda Yoga Anusandhana Samsthana Deemed University, Bengaluru 560 105, India
| | | | - Prashantha Kumar Bommenahally Ravanappa
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru 570 015, India and JSS Academy of Higher Education & Research, Mysuru, Karnataka, India;,Address correspondence to this author at the Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru 570 015, India and JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India; E-mail:
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26
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Recessive cerebellar and afferent ataxias - clinical challenges and future directions. Nat Rev Neurol 2022; 18:257-272. [PMID: 35332317 DOI: 10.1038/s41582-022-00634-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2022] [Indexed: 02/07/2023]
Abstract
Cerebellar and afferent ataxias present with a characteristic gait disorder that reflects cerebellar motor dysfunction and sensory loss. These disorders are a diagnostic challenge for clinicians because of the large number of acquired and inherited diseases that cause cerebellar and sensory neuron damage. Among such conditions that are recessively inherited, Friedreich ataxia and RFC1-associated cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) include the characteristic clinical, neuropathological and imaging features of ganglionopathies, a distinctive non-length-dependent type of sensory involvement. In this Review, we discuss the typical and atypical phenotypes of Friedreich ataxia and CANVAS, along with the features of other recessive ataxias that present with a ganglionopathy or polyneuropathy, with an emphasis on recently described clinical features, natural history and genotype-phenotype correlations. We review the main developments in understanding the complex pathology that affects the sensory neurons and cerebellum, which seem to be most vulnerable to disorders that affect mitochondrial function and DNA repair mechanisms. Finally, we discuss disease-modifying therapeutic advances in Friedreich ataxia, highlighting the most promising candidate molecules and lessons learned from previous clinical trials.
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27
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Rufini A, Malisan F, Condò I, Testi R. Drug Repositioning in Friedreich Ataxia. Front Neurosci 2022; 16:814445. [PMID: 35221903 PMCID: PMC8863941 DOI: 10.3389/fnins.2022.814445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 01/07/2022] [Indexed: 12/14/2022] Open
Abstract
Friedreich ataxia is a rare neurodegenerative disorder caused by insufficient levels of the essential mitochondrial protein frataxin. It is a severely debilitating disease that significantly impacts the quality of life of affected patients and reduces their life expectancy, however, an adequate cure is not yet available for patients. Frataxin function, although not thoroughly elucidated, is associated with assembly of iron-sulfur cluster and iron metabolism, therefore insufficient frataxin levels lead to reduced activity of many mitochondrial enzymes involved in the electron transport chain, impaired mitochondrial metabolism, reduced ATP production and inefficient anti-oxidant response. As a consequence, neurons progressively die and patients progressively lose their ability to coordinate movement and perform daily activities. Therapeutic strategies aim at restoring sufficient frataxin levels or at correcting some of the downstream consequences of frataxin deficiency. However, the classical pathways of drug discovery are challenging, require a significant amount of resources and time to reach the final approval, and present a high failure rate. Drug repositioning represents a viable alternative to boost the identification of a therapy, particularly for rare diseases where resources are often limited. In this review we will describe recent efforts aimed at the identification of a therapy for Friedreich ataxia through drug repositioning, and discuss the limitation of such strategies.
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Affiliation(s)
- Alessandra Rufini
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
- Fratagene Therapeutics, Rome, Italy
- Saint Camillus International University of Health and Medical Sciences, Rome, Italy
- *Correspondence: Alessandra Rufini,
| | - Florence Malisan
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
| | - Ivano Condò
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
| | - Roberto Testi
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
- Fratagene Therapeutics, Rome, Italy
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28
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Motley W, Chaudry V, Lloyd TE. Treatment and Management of Hereditary Neuropathies. Neuromuscul Disord 2022. [DOI: 10.1016/b978-0-323-71317-7.00014-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Harding IH, Lynch DR, Koeppen AH, Pandolfo M. Central Nervous System Therapeutic Targets in Friedreich Ataxia. Hum Gene Ther 2021; 31:1226-1236. [PMID: 33238751 PMCID: PMC7757690 DOI: 10.1089/hum.2020.264] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Friedreich ataxia (FRDA) is an autosomal recessive inherited multisystem disease, characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate. In the current era of expanding therapeutic discovery in FRDA, including progress toward novel gene therapies, a deeper and more specific consideration of potential treatment targets in the nervous system is necessary. In this work, we have re-examined the neuropathology of FRDA, recognizing new issues superimposed on classical findings, and dissected the peripheral nervous system (PNS) and central nervous system (CNS) aspects of the disease and the affected cell types. Understanding the temporal course of neuropathological changes is needed to identify areas of modifiable disease progression and the CNS and PNS locations that can be targeted at different time points. As most major targets of long-term therapy are in the CNS, this review uses multiple tools for evaluation of the importance of specific CNS locations as targets. In addition to clinical observations, the conceptualizations in this study include physiological, pathological, and imaging approaches, and animal models. We believe that this review, through analysis of a more complete set of data derived from multiple techniques, provides a comprehensive summary of therapeutic targets in FRDA.
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Affiliation(s)
- Ian H Harding
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia.,Monash Biomedical Imaging, Monash University, Melbourne, Australia
| | - David R Lynch
- Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Arnulf H Koeppen
- Research, Neurology, and Pathology Services, Veterans Affairs Medical Center and Departments of Neurology and Pathology, Albany Medical College, Albany, New York, USA
| | - Massimo Pandolfo
- Laboratory of Experimental Neurology, Université Libre de Bruxelles (ULB), Brussels, Belgium
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30
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Rodríguez-Pascau L, Vilalta A, Cerrada M, Traver E, Forss-Petter S, Weinhofer I, Bauer J, Kemp S, Pina G, Pascual S, Meya U, Musolino PL, Berger J, Martinell M, Pizcueta P. The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy. Sci Transl Med 2021; 13:13/596/eabc0555. [PMID: 34078742 DOI: 10.1126/scitranslmed.abc0555] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 08/06/2020] [Accepted: 03/18/2021] [Indexed: 12/19/2022]
Abstract
X-linked adrenoleukodystrophy (X-ALD), a potentially fatal neurometabolic disorder with no effective pharmacological treatment, is characterized by clinical manifestations ranging from progressive spinal cord axonopathy [adrenomyeloneuropathy (AMN)] to severe demyelination and neuroinflammation (cerebral ALD-cALD), for which molecular mechanisms are not well known. Leriglitazone is a recently developed brain penetrant full PPARγ agonist that could modulate multiple biological pathways relevant for neuroinflammatory and neurodegenerative diseases, and particularly for X-ALD. We found that leriglitazone decreased oxidative stress, increased adenosine 5'-triphosphate concentration, and exerted neuroprotective effects in primary rodent neurons and astrocytes after very long chain fatty acid-induced toxicity simulating X-ALD. In addition, leriglitazone improved motor function; restored markers of oxidative stress, mitochondrial function, and inflammation in spinal cord tissues from AMN mouse models; and decreased the neurological disability in the EAE neuroinflammatory mouse model. X-ALD monocyte-derived patient macrophages treated with leriglitazone were less skewed toward an inflammatory phenotype, and the adhesion of human X-ALD monocytes to brain endothelial cells decreased after treatment, suggesting the potential of leriglitazone to prevent the progression to pathologically disrupted blood-brain barrier. Leriglitazone increased myelin debris clearance in vitro and increased myelination and oligodendrocyte survival in demyelination-remyelination in vivo models, thus promoting remyelination. Last, leriglitazone was clinically tested in a phase 1 study showing central nervous system target engagement (adiponectin increase) and changes on inflammatory biomarkers in plasma and cerebrospinal fluid. The results of our study support the use of leriglitazone in X-ALD and, more generally, in other neuroinflammatory and neurodegenerative conditions.
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Affiliation(s)
| | - Anna Vilalta
- Minoryx Therapeutics S.L., Barcelona 08302, Spain
| | - Marc Cerrada
- Minoryx Therapeutics S.L., Barcelona 08302, Spain
| | | | - Sonja Forss-Petter
- Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna 1090, Austria
| | - Isabelle Weinhofer
- Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna 1090, Austria
| | - Jan Bauer
- Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna 1090, Austria
| | - Stephan Kemp
- Department of Clinical Chemistry and Pediatrics, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, Netherlands
| | - Guillem Pina
- Minoryx Therapeutics S.L., Barcelona 08302, Spain
| | | | - Uwe Meya
- Minoryx Therapeutics S.L., Barcelona 08302, Spain
| | - Patricia L Musolino
- Neurosciences Intensive Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Johannes Berger
- Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna 1090, Austria
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Chen HJ, Pan XX, Ding LLQ, Ruan CC, Gao PJ. Cardiac Fibroblast-Specific Knockout of PGC-1α Accelerates AngII-Induced Cardiac Remodeling. Front Cardiovasc Med 2021; 8:664626. [PMID: 34222364 PMCID: PMC8242582 DOI: 10.3389/fcvm.2021.664626] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 05/06/2021] [Indexed: 11/17/2022] Open
Abstract
Cardiac remodeling consisted of ventricular hypertrophy and interstitial fibrosis is the pathological process of many heart diseases. Fibroblasts as one of the major cells in the myocardium regulate the balance of the generation and degeneration of collagen, and these cells transform toward myofibroblasts in pathological state, contributing to the remodeling of the heart. Peroxisome proliferator-activated receptor-γ (PPAR-γ) coactivator-1α (PGC-1α) is vital to the function of mitochondria, which contributes to the energy production and reactive oxidative species (ROS)-scavenging activity in the heart. In this study, we found that fibroblast-specific PGC-1α KO induced cardiac remodeling especially fibrosis, and Angiotensin II (AngII) aggravated cardiac fibrosis, accompanied with a high level of oxidative stress response and inflammation.
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Affiliation(s)
- Hong-Jin Chen
- Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Xi Pan
- Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li-Li-Qiang Ding
- Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cheng-Chao Ruan
- Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ping-Jin Gao
- Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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All-trans retinoic acid reduces mammalian target of rapamycin via a Sirtuin1-dependent mechanism in neurons. Neuroreport 2021; 32:975-982. [PMID: 34050114 DOI: 10.1097/wnr.0000000000001672] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Neuroinflammation has emerged as a key contributor in the pathogenesis of Alzheimer's disease (AD). Mammalian target of rapamycin (mTOR) is a key regulator of metabolism, cell growth and protein synthesis. And an elevated mTOR activity has been detected in AD-affected brain areas. Previous studies have suggested that all-trans retinoic acid (atRA) and rapamycin (RAPA), an mTOR inhibitor, protect lipopolysaccharide (LPS)-induced neuronal inflammation through inhibiting nuclear import of NFκB. The aim of this study was to test the effects of atRA on mTOR expression. Here we discovered that mTOR and p-mTOR expression are elevated in LPS-treated mice or primary rat neurons, while atRA blocks the mTOR gene upregulation via a SIRT1-dependent mechanism. The results of this study demonstrated that atRA may protect LPS-induced neuronal inflammation through suppressing mTOR signaling.
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Wu M, Zhang C, Xie M, Zhen Y, Lai B, Liu J, Qiao L, Liu S, Shi D. Compartmentally scavenging hepatic oxidants through AMPK/SIRT3-PGC1α axis improves mitochondrial biogenesis and glucose catabolism. Free Radic Biol Med 2021; 168:117-128. [PMID: 33794310 DOI: 10.1016/j.freeradbiomed.2021.03.029] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 03/16/2021] [Accepted: 03/24/2021] [Indexed: 01/27/2023]
Abstract
Early treatment can prevent the occurrence of diabetes; however, there are few pharmacological treatment strategies to date. The liver is a major metabolic organ, and hepatic glucose homeostasis is dysregulated in type 1 and type 2 diabetes mellitus. However, the potential of specifically targeting the liver to prevent diabetes has not been fully exploited. In this study, we found that compartmentally inhibiting hepatic oxidants by nano-MitoPBN, a liver mitochondrial-targeting ROS scavenger, could effectively prevent diabetes. Our results demonstrated that nano-MitoPBN reversed the downregulation of PGC-1α and the enhanced gluconeogenesis in the livers of diabetic mice. PGC-1α, through an AMPK- and SIRT3-mediated mechanism, promoted mitochondrial biogenesis, increased the number of mitochondria, and enhanced the rate of aerobic oxidation, leading to decreased glucose levels in the blood by increasing glucose uptake and catabolism in the liver. Moreover, the increase in PGC-1α activity did not promote the activation of gluconeogenesis. Our study demonstrated that by regulating the redox balance of liver mitochondria in the early stage of diabetes, PGC-1α could selectively inhibit gluconeogenesis in the liver and promote hepatic mitochondrial function, which accelerated the catabolism of hepatic glucose and reduced blood glucose. Thus, glucose tolerance can be normalized through only three weeks of intervention. Our results showed that nano-MitoPBN could effectively prevent diabetes in a short period of time, highlighting the effectiveness and importance of early intervention for diabetes and suggesting the potential advantages of hepatic mitochondrial targeting oxidants nano-inhibitors in the prevention and early treatment of diabetes.
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Affiliation(s)
- Meiling Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Chunwang Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Mengdan Xie
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Yuansheng Zhen
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Ben Lai
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Jiankang Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Liang Qiao
- Department of Chemistry, Fudan University, Shanghai, 200433, People's Republic of China
| | - Shanlin Liu
- Free Radical Regulation and Application Research Center of Fudan University, Shanghai, 200032, People's Republic of China.
| | - Dongyun Shi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China.
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Mitochondrial and metabolic dysfunction in Friedreich ataxia: update on pathophysiological relevance and clinical interventions. Neuronal Signal 2021; 5:NS20200093. [PMID: 34046211 PMCID: PMC8132591 DOI: 10.1042/ns20200093] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/29/2021] [Accepted: 04/30/2021] [Indexed: 02/07/2023] Open
Abstract
Friedreich ataxia (FRDA) is a recessive disorder resulting from relative deficiency of the mitochondrial protein frataxin. Frataxin functions in the process of iron–sulfur (Fe–S) cluster synthesis. In this review, we update some of the processes downstream of frataxin deficiency that may mediate the pathophysiology. Based on cellular models, in vivo models and observations of patients, ferroptosis may play a major role in the pathogenesis of FRDA along with depletion of antioxidant reserves and abnormalities of mitochondrial biogenesis. Ongoing clinical trials with ferroptosis inhibitors and nuclear factor erythroid 2-related factor 2 (Nrf2) activators are now targeting each of the processes. In addition, better understanding of the mitochondrial events in FRDA may allow the development of improved imaging methodology for assessing the disorder. Though not technologically feasible at present, metabolic imaging approaches may provide a direct methodology to understand the mitochondrial changes occurring in FRDA and provide a methodology to monitor upcoming trials of frataxin restoration.
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Sanchez Caballero L, Gorgogietas V, Arroyo MN, Igoillo-Esteve M. Molecular mechanisms of β-cell dysfunction and death in monogenic forms of diabetes. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 359:139-256. [PMID: 33832649 DOI: 10.1016/bs.ircmb.2021.02.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Monogenetic forms of diabetes represent 1%-5% of all diabetes cases and are caused by mutations in a single gene. These mutations, that affect genes involved in pancreatic β-cell development, function and survival, or insulin regulation, may be dominant or recessive, inherited or de novo. Most patients with monogenic diabetes are very commonly misdiagnosed as having type 1 or type 2 diabetes. The severity of their symptoms depends on the nature of the mutation, the function of the affected gene and, in some cases, the influence of additional genetic or environmental factors that modulate severity and penetrance. In some patients, diabetes is accompanied by other syndromic features such as deafness, blindness, microcephaly, liver and intestinal defects, among others. The age of diabetes onset may also vary from neonatal until early adulthood manifestations. Since the different mutations result in diverse clinical presentations, patients usually need different treatments that range from just diet and exercise, to the requirement of exogenous insulin or other hypoglycemic drugs, e.g., sulfonylureas or glucagon-like peptide 1 analogs to control their glycemia. As a consequence, awareness and correct diagnosis are crucial for the proper management and treatment of monogenic diabetes patients. In this chapter, we describe mutations causing different monogenic forms of diabetes associated with inadequate pancreas development or impaired β-cell function and survival, and discuss the molecular mechanisms involved in β-cell demise.
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Affiliation(s)
- Laura Sanchez Caballero
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Vyron Gorgogietas
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Maria Nicol Arroyo
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Mariana Igoillo-Esteve
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/.
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Lynch DR, Johnson J. Omaveloxolone: potential new agent for Friedreich ataxia. Neurodegener Dis Manag 2021; 11:91-98. [PMID: 33430645 DOI: 10.2217/nmt-2020-0057] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Friedreich ataxia is a slowly progressive neurodegenerative disorder leading to ataxia, dyscoordination, dysarthria and in many individuals vision and hearing loss. It is associated with cardiomyopathy, the leading cause of death in Friedreich ataxia (FRDA), diabetes and scoliosis. There are no approved therapies, but elucidation of the pathophysiology of FRDA suggest that agents that increase the activity of the transcription factor Nrf2 may provide a mechanism for ameliorating disease progression or severity. In this work, we review the evidence for use of omaveloxolone in FRDA from recent clinical trials. Though not at present approved for any indication, the present data suggest that this agent acting though increases in Nrf2 activity may provide a novel therapy for FRDA.
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Affiliation(s)
- David R Lynch
- Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.,Department of Neurology & Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Joseph Johnson
- Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.,Department of Systems Pharmacology & Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA
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Rodríguez-Pascau L, Britti E, Calap-Quintana P, Dong YN, Vergara C, Delaspre F, Medina-Carbonero M, Tamarit J, Pallardó FV, Gonzalez-Cabo P, Ros J, Lynch DR, Martinell M, Pizcueta P. PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia. Neurobiol Dis 2021; 148:105162. [PMID: 33171227 DOI: 10.1016/j.nbd.2020.105162] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/14/2020] [Accepted: 11/03/2020] [Indexed: 01/08/2023] Open
Abstract
Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy, and increased incidence in diabetes. The underlying pathophysiological mechanism of FRDA, driven by a significantly decreased expression of frataxin (FXN), involves increased oxidative stress, reduced activity of enzymes containing iron‑sulfur clusters (ISC), defective energy production, calcium dyshomeostasis, and impaired mitochondrial biogenesis, leading to mitochondrial dysfunction. The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcriptional factor playing a key role in mitochondrial function and biogenesis, fatty acid storage, energy metabolism, and antioxidant defence. It has been previously shown that the PPARγ/PPARγ coactivator 1 alpha (PGC-1α) pathway is dysregulated when there is frataxin deficiency, thus contributing to FRDA pathogenesis and supporting the PPARγ pathway as a potential therapeutic target. Here we assess whether MIN-102 (INN: leriglitazone), a novel brain penetrant and orally bioavailable PPARγ agonist with an improved profile for central nervous system (CNS) diseases, rescues phenotypic features in cellular and animal models of FRDA. In frataxin-deficient dorsal root ganglia (DRG) neurons, leriglitazone increased frataxin protein levels, reduced neurite degeneration and α-fodrin cleavage mediated by calpain and caspase 3, and increased survival. Leriglitazone also restored mitochondrial membrane potential and partially reversed decreased levels of mitochondrial Na+/Ca2+ exchanger (NCLX), resulting in an improvement of mitochondrial functions and calcium homeostasis. In frataxin-deficient primary neonatal cardiomyocytes, leriglitazone prevented lipid droplet accumulation without increases in frataxin levels. Furthermore, leriglitazone improved motor function deficit in YG8sR mice, a FRDA mouse model. In agreement with the role of PPARγ in mitochondrial biogenesis, leriglitazone significantly increased markers of mitochondrial biogenesis in FRDA patient cells. Overall, these results suggest that targeting the PPARγ pathway by leriglitazone may provide an efficacious therapy for FRDA increasing the mitochondrial function and biogenesis that could increase frataxin levels in compromised frataxin-deficient DRG neurons. Alternately, leriglitazone improved the energy metabolism by increasing the fatty acid β-oxidation in frataxin-deficient cardiomyocytes without elevation of frataxin levels. This could be linked to a lack of significant mitochondrial biogenesis and cardiac hypertrophy. The results reinforced the different tissue requirement in FRDA and the pleiotropic effects of leriglitazone that could be a promising therapy for FRDA.
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Affiliation(s)
| | - Elena Britti
- Departament de Ciències Mèdiques Bàsiques, IRBLleida. Universitat de Lleida, Lleida 25198, Spain
| | - Pablo Calap-Quintana
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia-INCLIVA, Valencia 46010, Spain; CIBER de Enfermedades Raras (CIBERER), Valencia, Spain
| | - Yi Na Dong
- Department of Pediatrics and Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | | | - Fabien Delaspre
- Departament de Ciències Mèdiques Bàsiques, IRBLleida. Universitat de Lleida, Lleida 25198, Spain
| | - Marta Medina-Carbonero
- Departament de Ciències Mèdiques Bàsiques, IRBLleida. Universitat de Lleida, Lleida 25198, Spain
| | - Jordi Tamarit
- Departament de Ciències Mèdiques Bàsiques, IRBLleida. Universitat de Lleida, Lleida 25198, Spain
| | - Federico V Pallardó
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia-INCLIVA, Valencia 46010, Spain; CIBER de Enfermedades Raras (CIBERER), Valencia, Spain
| | - Pilar Gonzalez-Cabo
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia-INCLIVA, Valencia 46010, Spain; CIBER de Enfermedades Raras (CIBERER), Valencia, Spain
| | - Joaquim Ros
- Departament de Ciències Mèdiques Bàsiques, IRBLleida. Universitat de Lleida, Lleida 25198, Spain
| | - David R Lynch
- Department of Pediatrics and Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Marc Martinell
- Minoryx Therapeutics SL., Mataró 08302, Barcelona, Spain; Minoryx Therapeutics BE., Gosselies 6041, Charleroi, Belgium
| | - Pilar Pizcueta
- Minoryx Therapeutics SL., Mataró 08302, Barcelona, Spain.
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Mitochondrial dysfunction in the development and progression of neurodegenerative diseases. Arch Biochem Biophys 2020; 702:108698. [PMID: 33259796 DOI: 10.1016/j.abb.2020.108698] [Citation(s) in RCA: 145] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/11/2020] [Accepted: 11/21/2020] [Indexed: 02/07/2023]
Abstract
In addition to ATP synthesis, mitochondria are highly dynamic organelles that modulate apoptosis, ferroptosis, and inflammasome activation. Through executing these varied functions, the mitochondria play critical roles in the development and progression of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Friedreich ataxia, among others. Impaired mitochondrial biogenesis and abnormal mitochondrial dynamics contribute to mitochondrial dysfunction in these diseases. Additionally, dysfunctional mitochondria play critical roles in signaling for both inflammasome activation and ferroptosis. Therapeutics are being developed to circumvent inflammasome activation and ferroptosis in dysfunctional mitochondria. Targeting these aspects of mitochondrial dysfunction may present viable therapeutic strategies for combatting the neurodegenerative diseases. This review aims to summarize the role of the mitochondria in the development and progression of neurodegenerative diseases and to present current therapeutic approaches that target mitochondrial dysfunction in these diseases.
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Jagust P, Alcalá S, Jr BS, Heeschen C, Sancho P. Glutathione metabolism is essential for self-renewal and chemoresistance of pancreatic cancer stem cells. World J Stem Cells 2020; 12:1410-1428. [PMID: 33312407 PMCID: PMC7705467 DOI: 10.4252/wjsc.v12.i11.1410] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/19/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cellular metabolism regulates stemness in health and disease. A reduced redox state is essential for self-renewal of normal and cancer stem cells (CSCs). However, while stem cells rely on glycolysis, different CSCs, including pancreatic CSCs, favor mitochondrial metabolism as their dominant energy-producing pathway. This suggests that powerful antioxidant networks must be in place to detoxify mitochondrial reactive oxygen species (ROS) and maintain stemness in oxidative CSCs. Since glutathione metabolism is critical for normal stem cell function and CSCs from breast, liver and gastric cancer show increased glutathione content, we hypothesized that pancreatic CSCs also rely on this pathway for ROS detoxification.
AIM To investigate the role of glutathione metabolism in pancreatic CSCs.
METHODS Primary pancreatic cancer cells of patient-derived xenografts (PDXs) were cultured in adherent or CSC-enriching sphere conditions to determine the role of glutathione metabolism in stemness. Real-time polymerase chain reaction (PCR) was used to validate RNAseq results involving glutathione metabolism genes in adherent vs spheres, as well as the expression of pluripotency-related genes following treatment. Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2. The glutathione-sensitive fluorescent probe monochlorobimane was used to determine glutathione content by fluorimetry or flow cytometry. Pharmacological inhibitors of glutathione synthesis and recycling [buthionine-sulfoximine (BSO) and 6-Aminonicotinamide (6-AN), respectively] were used to investigate the impact of glutathione depletion on CSC-enriched cultures. Staining with propidium iodide (cell cycle), Annexin-V (apoptosis) and CD133 (CSC content) were determined by flow cytometry. Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.
RESULTS Analysis of our previously published RNAseq dataset E-MTAB-3808 revealed up-regulation of genes involved in the KEGG (Kyoto Encyclopedia of Genes and Genomes) Pathway Glutathione Metabolism in CSC-enriched cultures compared to their differentiated counterparts. Consistently, in pancreatic cancer patient samples the expression of most of these up-regulated genes positively correlated with a stemness signature defined by NANOG, KLF4, SOX2 and OCT4 expression (P < 10-5). Moreover, 3 of the upregulated genes (MGST1, GPX8, GCCT) were associated with reduced disease-free survival in patients [Hazard ratio (HR) 2.2-2.5; P = 0.03-0.0054], suggesting a critical role for this pathway in pancreatic cancer progression. CSC-enriched sphere cultures also showed increased expression of different glutathione metabolism-related genes, as well as enhanced glutathione content in its reduced form (GSH). Glutathione depletion with BSO induced cell cycle arrest and apoptosis in spheres, and diminished the expression of stemness genes. Moreover, treatment with either BSO or the glutathione recycling inhibitor 6-AN inhibited self-renewal and the expression of the CSC marker CD133. GSH content in spheres positively correlated with intrinsic resistance to gemcitabine treatment in different PDXs r = 0.96, P = 5.8 × 1011). Additionally, CD133+ cells accumulated GSH in response to gemcitabine, which was abrogated by BSO treatment (P < 0.05). Combined treatment with BSO and gemcitabine-induced apoptosis in CD133+ cells to levels comparable to CD133- cells and significantly diminished self-renewal (P < 0.05), suggesting that chemoresistance of CSCs is partially dependent on GSH metabolism.
CONCLUSION Our data suggest that pancreatic CSCs depend on glutathione metabolism. Pharmacological targeting of this pathway showed that high GSH content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance.
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Affiliation(s)
- Petra Jagust
- Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain
| | - Sonia Alcalá
- Department of Biochemistry, Autónoma University of Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid 28029, Spain
| | - Bruno Sainz Jr
- Department of Biochemistry, Autónoma University of Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid 28029, Spain
| | - Christopher Heeschen
- Center for Single-Cell Omics & Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Patricia Sancho
- Hospital Universitario Miguel Servet, IIS Aragon, Zaragoza 50009, Spain
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Smith FM, Kosman DJ. Molecular Defects in Friedreich's Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities. Front Mol Biosci 2020; 7:569293. [PMID: 33263002 PMCID: PMC7686857 DOI: 10.3389/fmolb.2020.569293] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 09/10/2020] [Indexed: 01/18/2023] Open
Abstract
Friedreich’s ataxia (FRDA) is a multi-faceted disease characterized by progressive sensory–motor loss, neurodegeneration, brain iron accumulation, and eventual death by hypertrophic cardiomyopathy. FRDA follows loss of frataxin (FXN), a mitochondrial chaperone protein required for incorporation of iron into iron–sulfur cluster and heme precursors. After the discovery of the molecular basis of FRDA in 1996, over two decades of research have been dedicated to understanding the temporal manifestations of disease both at the whole body and molecular level. Early research indicated strong cellular iron dysregulation in both human and yeast models followed by onset of oxidative stress. Since then, the pathophysiology due to dysregulation of intracellular iron chaperoning has become central in FRDA relative to antioxidant defense and run-down in energy metabolism. At the same time, limited consideration has been given to changes in cytoskeletal organization, which was one of the first molecular defects noted. These alterations include both post-translational oxidative glutathionylation of actin monomers and differential DNA processing of a cytoskeletal regulator PIP5K1β. Currently unknown in respect to FRDA but well understood in the context of FXN-deficient cell physiology is the resulting impact on the cytoskeleton; this disassembly of actin filaments has a particularly profound effect on cell–cell junctions characteristic of barrier cells. With respect to a neurodegenerative disorder such as FRDA, this cytoskeletal and tight junction breakdown in the brain microvascular endothelial cells of the blood–brain barrier is likely a component of disease etiology. This review serves to outline a brief history of this research and hones in on pathway dysregulation downstream of iron-related pathology in FRDA related to actin dynamics. The review presented here was not written with the intent of being exhaustive, but to instead urge the reader to consider the essentiality of the cytoskeleton and appreciate the limited knowledge on FRDA-related cytoskeletal dysfunction as a result of oxidative stress. The review examines previous hypotheses of neurodegeneration with brain iron accumulation (NBIA) in FRDA with a specific biochemical focus.
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Affiliation(s)
- Frances M Smith
- Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, United States
| | - Daniel J Kosman
- Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, United States
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Rodríguez LR, Lapeña T, Calap-Quintana P, Moltó MD, Gonzalez-Cabo P, Navarro Langa JA. Antioxidant Therapies and Oxidative Stress in Friedreich´s Ataxia: The Right Path or Just a Diversion? Antioxidants (Basel) 2020; 9:E664. [PMID: 32722309 PMCID: PMC7465446 DOI: 10.3390/antiox9080664] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/17/2020] [Accepted: 07/19/2020] [Indexed: 12/12/2022] Open
Abstract
Friedreich´s ataxia is the commonest autosomal recessive ataxia among population of European descent. Despite the huge advances performed in the last decades, a cure still remains elusive. One of the most studied hallmarks of the disease is the increased production of oxidative stress markers in patients and models. This feature has been the motivation to develop treatments that aim to counteract such boost of free radicals and to enhance the production of antioxidant defenses. In this work, we present and critically review those "antioxidant" drugs that went beyond the disease´s models and were approved for its application in clinical trials. The evaluation of these trials highlights some crucial aspects of the FRDA research. On the one hand, the analysis contributes to elucidate whether oxidative stress plays a central role or whether it is only an epiphenomenon. On the other hand, it comments on some limitations in the current trials that complicate the analysis and interpretation of their outcome. We also include some suggestions that will be interesting to implement in future studies and clinical trials.
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Affiliation(s)
- Laura R. Rodríguez
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
| | - Tamara Lapeña
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
| | - Pablo Calap-Quintana
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
| | - María Dolores Moltó
- Department of Genetics, Universitat de València-INCLIVA, 46100 Valencia, Spain;
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 46100 Valencia, Spain
| | - Pilar Gonzalez-Cabo
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
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Suntar I, Sureda A, Belwal T, Sanches Silva A, Vacca RA, Tewari D, Sobarzo-Sánchez E, Nabavi SF, Shirooie S, Dehpour AR, Xu S, Yousefi B, Majidinia M, Daglia M, D'Antona G, Nabavi SM. Natural products, PGC-1 α , and Duchenne muscular dystrophy. Acta Pharm Sin B 2020; 10:734-745. [PMID: 32528825 PMCID: PMC7276681 DOI: 10.1016/j.apsb.2020.01.001] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 10/14/2019] [Accepted: 12/06/2019] [Indexed: 02/08/2023] Open
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a transcriptional coactivator that binds to a diverse range of transcription factors. PPARγ coactivator 1 (PGC-1) coactivators possess an extensive range of biological effects in different tissues, and play a key part in the regulation of the oxidative metabolism, consequently modulating the production of reactive oxygen species, autophagy, and mitochondrial biogenesis. Owing to these findings, a large body of studies, aiming to establish the role of PGC-1 in the neuromuscular system, has shown that PGC-1 could be a promising target for therapies targeting neuromuscular diseases. Among these, some evidence has shown that various signaling pathways linked to PGC-1α are deregulated in muscular dystrophy, leading to a reduced capacity for mitochondrial oxidative phosphorylation and increased reactive oxygen species (ROS) production. In the light of these results, any intervention aimed at activating PGC-1 could contribute towards ameliorating the progression of muscular dystrophies. PGC-1α is influenced by different patho-physiological/pharmacological stimuli. Natural products have been reported to display modulatory effects on PPARγ activation with fewer side effects in comparison to synthetic drugs. Taken together, this review summarizes the current knowledge on Duchenne muscular dystrophy, focusing on the potential effects of natural compounds, acting as regulators of PGC-1α.
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Key Words
- AAV, adeno-associated virus
- AMP, adenosine monophosphate
- AMPK, 5′ adenosine monophosphate-activated protein kinase
- ASO, antisense oligonucleotides
- ATF2, activating transcription factor 2
- ATP, adenosine triphosphate
- BMD, Becker muscular dystrophy
- COPD, chronic obstructive pulmonary disease
- CREB, cyclic AMP response element-binding protein
- CnA, calcineurin a
- DAGC, dystrophin-associated glycoprotein complex
- DGC, dystrophin–glycoprotein complex
- DMD, Duchenne muscular dystrophy
- DRP1, dynamin-related protein 1
- DS, Down syndrome
- ECM, extracellular matrix
- EGCG, epigallocatechin-3-gallate
- ERRα, estrogen-related receptor alpha
- FDA, U. S. Food and Drug Administration
- FGF, fibroblast growth factor
- FOXO1, forkhead box class-O1
- GABP, GA-binding protein
- GPX, glutathione peroxidase
- GSK3b, glycogen synthase kinase 3b
- HCT, hydrochlorothiazide
- HDAC, histone deacetylase
- HIF-1α, hypoxia-inducible factors
- IL, interleukin
- LDH, lactate dehydrogenase
- MCP-1, monocyte chemoattractant protein-1
- MD, muscular dystrophy
- MEF2, myocyte enhancer factor 2
- MSCs, mesenchymal stem cells
- Mitochondrial oxidative phosphorylation
- Muscular dystrophy
- MyoD, myogenic differentiation
- NADPH, nicotinamide adenine dinucleotide phosphate
- NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells
- NMJ, neuromuscular junctions
- NO, nitric oxide
- NOS, NO synthase
- Natural product
- PDGF, platelet derived growth factor
- PGC-1, peroxisome proliferator-activated receptor γ coactivator 1
- PPARγ activation
- PPARγ, peroxisome proliferator-activated receptor γ
- Peroxisome proliferator-activated receptor γ coactivator 1α
- ROS, reactive oxygen species
- Reactive oxygen species
- SIRT1, silent mating type information regulation 2 homolog 1
- SOD, superoxide dismutase
- SPP1, secreted phosphoprotein 1
- TNF-α, tumor necrosis factor-α
- UCP, uncoupling protein
- VEGF, vascular endothelial growth factor
- cGMP, cyclic guanosine monophosphate
- iPSCs, induced pluripotent stem cells
- p38 MAPK, p38 mitogen-activated protein kinase
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Tiano F, Amati F, Cherubini F, Morini E, Vancheri C, Maletta S, Fortuni S, Serio D, Quatrana A, Luffarelli R, Benini M, Alfedi G, Panarello L, Rufini A, Toschi N, Frontali M, Romano S, Marcotulli C, Casali C, Gioiosa S, Mariotti C, Mongelli A, Fichera M, Condò I, Novelli G, Testi R, Malisan F. Frataxin deficiency in Friedreich's ataxia is associated with reduced levels of HAX-1, a regulator of cardiomyocyte death and survival. Hum Mol Genet 2020; 29:471-482. [PMID: 31943004 DOI: 10.1093/hmg/ddz306] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 11/29/2019] [Accepted: 12/10/2019] [Indexed: 12/31/2022] Open
Abstract
Frataxin deficiency, responsible for Friedreich's ataxia (FRDA), is crucial for cell survival since it critically affects viability of neurons, pancreatic beta cells and cardiomyocytes. In FRDA, the heart is frequently affected with typical manifestation of hypertrophic cardiomyopathy, which can progress to heart failure and cause premature death. A microarray analysis performed on FRDA patient's lymphoblastoid cells stably reconstituted with frataxin, indicated HS-1-associated protein X-1 (HAX-1) as the most significantly upregulated transcript (FC = +2, P < 0.0006). quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) and western blot analysis performed on (I) HEK293 stably transfected with empty vector compared to wild-type frataxin and (II) lymphoblasts from FRDA patients show that low frataxin mRNA and protein expression correspond to reduced levels of HAX-1. Frataxin overexpression and silencing were also performed in the AC16 human cardiomyocyte cell line. HAX-1 protein levels are indeed regulated through frataxin modulation. Moreover, correlation between frataxin and HAX-1 was further evaluated in peripheral blood mononuclear cells (PBMCs) from FRDA patients and from non-related healthy controls. A regression model for frataxin which included HAX-1, group membership and group* HAX-1 interaction revealed that frataxin and HAX-1 are associated both at mRNA and protein levels. Additionally, a linked expression of FXN, HAX-1 and antioxidant defence proteins MnSOD and Nrf2 was observed both in PBMCs and AC16 cardiomyocytes. Our results suggest that HAX-1 could be considered as a potential biomarker of cardiac disease in FRDA and the evaluation of its expression might provide insights into its pathogenesis as well as improving risk stratification strategies.
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Affiliation(s)
- Francesca Tiano
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Francesca Amati
- Section of Medical Genetics, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- Department of Human Sciences and Quality of Life Promotion, University San Raffaele, 00166 Rome, Italy
| | - Fabio Cherubini
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Elena Morini
- Section of Medical Genetics, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Chiara Vancheri
- Section of Medical Genetics, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Sara Maletta
- Section of Medical Genetics, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Silvia Fortuni
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Dario Serio
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Andrea Quatrana
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Riccardo Luffarelli
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- Fratagene Therapeutics Srl, 00133 Rome, Italy
| | - Monica Benini
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- Fratagene Therapeutics Srl, 00133 Rome, Italy
| | - Giulia Alfedi
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- Fratagene Therapeutics Srl, 00133 Rome, Italy
| | - Luca Panarello
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Alessandra Rufini
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- Fratagene Therapeutics Srl, 00133 Rome, Italy
| | - Nicola Toschi
- Medical Physics Section, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- A.A. Martinos Center for Biomedical Imaging, Harvard Medical School, Charlestown, MA 02129, USA
| | - Marina Frontali
- CNR Institute of Translational Pharmacology, 00133 Rome, Italy
| | - Silvia Romano
- Neurosciences, Mental Health and Sensory Organs (NESMOS) Department, Faculty of Medicine and Psychology, Sapienza University, 00189 Rome, Italy
| | - Christian Marcotulli
- Department of Medical Surgical Sciences and Biotechnologies, Polo Pontino-Sapienza University of Rome, 04100 Latina, Italy
| | - Carlo Casali
- Department of Medical Surgical Sciences and Biotechnologies, Polo Pontino-Sapienza University of Rome, 04100 Latina, Italy
| | - Silvia Gioiosa
- SCAI (Super Computing Applications and Innovations) CINECA, 00185 Rome, Italy
| | - Caterina Mariotti
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
| | - Alessia Mongelli
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
| | - Mario Fichera
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
| | - Ivano Condò
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
| | - Giuseppe Novelli
- Section of Medical Genetics, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- Neuromed Institute, IRCCS, 86077 Pozzilli, Italy
| | - Roberto Testi
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
- Fratagene Therapeutics Srl, 00133 Rome, Italy
| | - Florence Malisan
- Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," 00133 Rome, Italy
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44
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Oka SI, Sabry AD, Cawley KM, Warren JS. Multiple Levels of PGC-1α Dysregulation in Heart Failure. Front Cardiovasc Med 2020; 7:2. [PMID: 32083094 PMCID: PMC7002390 DOI: 10.3389/fcvm.2020.00002] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 01/08/2020] [Indexed: 12/13/2022] Open
Abstract
Metabolic adaption is crucial for the heart to sustain its contractile activity under various physiological and pathological conditions. At the molecular level, the changes in energy demand impinge on the expression of genes encoding for metabolic enzymes. Among the major components of an intricate transcriptional circuitry, peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α) plays a critical role as a metabolic sensor, which is responsible for the fine-tuning of transcriptional responses to a plethora of stimuli. Cumulative evidence suggests that energetic impairment in heart failure is largely attributed to the dysregulation of PGC-1α. In this review, we summarize recent studies revealing how PGC-1α is regulated by a multitude of mechanisms, operating at different regulatory levels, which include epigenetic regulation, the expression of variants, post-transcriptional inhibition, and post-translational modifications. We further discuss how the PGC-1α regulatory cascade can be impaired in the failing heart.
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Affiliation(s)
- Shin-Ichi Oka
- Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ, United States
| | - Amira D Sabry
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, United States
| | - Keiko M Cawley
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, United States
| | - Junco S Warren
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, United States.,Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States.,Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan
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45
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Justin A, Mandal S, Prabitha P, Dhivya S, Yuvaraj S, Kabadi P, Sekhar SJ, Sandhya CH, Wadhwani AD, Divakar S, Bharathi JJ, Durai P, Prashantha Kumar BR. Rational Design, Synthesis, and In Vitro Neuroprotective Evaluation of Novel Glitazones for PGC-1α Activation via PPAR-γ: a New Therapeutic Strategy for Neurodegenerative Disorders. Neurotox Res 2019; 37:508-524. [DOI: 10.1007/s12640-019-00132-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 10/16/2019] [Accepted: 10/25/2019] [Indexed: 12/19/2022]
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46
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Choi HI, Park JS, Kim DH, Kim CS, Bae EH, Ma SK, Kim SW. PGC-1α Suppresses the Activation of TGF-β/Smad Signaling via Targeting TGFβRI Downregulation by let-7b/c Upregulation. Int J Mol Sci 2019; 20:5084. [PMID: 31614978 PMCID: PMC6829475 DOI: 10.3390/ijms20205084] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 10/04/2019] [Accepted: 10/10/2019] [Indexed: 01/04/2023] Open
Abstract
TGF-β/Smad signaling is a major pathway in progressive fibrotic processes, and further studies on the molecular mechanisms of TGF-β/Smad signaling are still needed for their therapeutic targeting. Recently, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) was shown to improve renal fibrosis, making it an attractive target for chronic kidney diseases (CKDs). Here, we show the mechanism by which PGC-1α regulates the TGF-β/Smad signaling pathway using HK-2 cell lines stably overexpressing empty vector (mock cells) or human PGC1α (PGC1α cells). Stable PGC-1α overexpression negatively regulated the expression of TGF-β-induced epithelial-mesenchymal transition (EMT) markers (fibronectin, E-cadherin, vimentin, and α-SMA) and EMT-related transcription factors (Snail and Slug) compared to mock cells, inhibiting fibrotic progression. Interestingly, among molecules upstream of Smad2/3 activation, the gene expression of only TGFβRI, but not TGFβRII, was downregulated in PGC-1α cells. In addition, the downregulation of TGFβRI by PGC-1α was associated with the upregulation of let-7b/c, miRNA for which the 3' untranslated region (UTR) of TGFβRI contains a binding site. In conclusion, PGC-1α suppresses TGF-β/Smad signaling activation via targeting TGFβRI downregulation by let-7b/c upregulation.
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Affiliation(s)
- Hoon-In Choi
- Department of Internal Medicine, Chonnam National University Medical School, 42 Jebongro, Gwangju 61469, Korea.
| | - Jung Sun Park
- Department of Internal Medicine, Chonnam National University Medical School, 42 Jebongro, Gwangju 61469, Korea.
| | - Dong-Hyun Kim
- Department of Internal Medicine, Chonnam National University Medical School, 42 Jebongro, Gwangju 61469, Korea.
| | - Chang Seong Kim
- Department of Internal Medicine, Chonnam National University Medical School, 42 Jebongro, Gwangju 61469, Korea.
| | - Eun Hui Bae
- Department of Internal Medicine, Chonnam National University Medical School, 42 Jebongro, Gwangju 61469, Korea.
| | - Seong Kwon Ma
- Department of Internal Medicine, Chonnam National University Medical School, 42 Jebongro, Gwangju 61469, Korea.
| | - Soo Wan Kim
- Department of Internal Medicine, Chonnam National University Medical School, 42 Jebongro, Gwangju 61469, Korea.
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47
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Li J, Rozwadowska N, Clark A, Fil D, Napierala JS, Napierala M. Excision of the expanded GAA repeats corrects cardiomyopathy phenotypes of iPSC-derived Friedreich's ataxia cardiomyocytes. Stem Cell Res 2019; 40:101529. [PMID: 31446150 PMCID: PMC6853280 DOI: 10.1016/j.scr.2019.101529] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 08/02/2019] [Accepted: 08/05/2019] [Indexed: 02/06/2023] Open
Abstract
Friedreich's ataxia is caused by large homozygous, intronic expansions of GAA repeats in the frataxin (FXN) gene, resulting in severe downregulation of its expression. Pathogenic repeats are located in intron one, hence patients express unaffected FXN protein, albeit in low quantities. Although FRDA symptoms typically afflict the nervous system, hypertrophic cardiomyopathy is the predominant cause of death. Our studies were conducted using cardiomyocytes differentiated from induced pluripotent stem cells derived from control individuals, FRDA patients, and isogenic cells corrected by zinc finger nucleases-mediated excision of pathogenic expanded GAA repeats. This correction of the FXN gene removed the primary trigger of the transcription defect, upregulated frataxin expression, reduced pathological lipid accumulation observed in patient cardiomyocytes, and reversed gene expression signatures of FRDA cardiomyocytes. Transcriptome analyses revealed hypertrophy-specific expression signatures unique to FRDA cardiomyocytes, and emphasized similarities between unaffected and ZFN-corrected FRDA cardiomyocytes. Thus, the iPSC-derived FRDA cardiomyocytes exhibit various molecular defects characteristic for cellular models of cardiomyopathy that can be corrected by genome editing of the expanded GAA repeats. These results underscore the utility of genome editing in generating isogenic cellular models of FRDA and the potential of this approach as a future therapy for this disease.
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Affiliation(s)
- Jixue Li
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL 35294, USA
| | - Natalia Rozwadowska
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL 35294, USA
| | - Amanda Clark
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL 35294, USA
| | - Daniel Fil
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL 35294, USA
| | - Jill S Napierala
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL 35294, USA.
| | - Marek Napierala
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL 35294, USA.
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Zeng R, Wang X, Zhou Q, Fu X, Wu Q, Lu Y, Shi J, Klaunig JE, Zhou S. Icariin protects rotenone-induced neurotoxicity through induction of SIRT3. Toxicol Appl Pharmacol 2019; 379:114639. [DOI: 10.1016/j.taap.2019.114639] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 06/21/2019] [Accepted: 06/23/2019] [Indexed: 12/28/2022]
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Targeting Mitochondrial Defects to Increase Longevity in Animal Models of Neurodegenerative Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1134:89-110. [PMID: 30919333 DOI: 10.1007/978-3-030-12668-1_5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Bioenergetic homeostasis is a vital process maintaining cellular health and has primary importance in neuronal cells due to their high energy demand markedly at synapses. Mitochondria, the metabolic hubs of the cells, are the organelles responsible for producing energy in the form of ATP by using nutrients and oxygen. Defects in mitochondrial homeostasis result in energy deprivation and can lead to disrupted neuronal functions. Mitochondrial defects adversely contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD). Mitochondrial defects not only include reduced ATP levels but also increased reactive oxygen species (ROS) leading to cellular damage. Here, we detail the mechanisms that lead to neuronal pathologies involving mitochondrial defects. Furthermore, we discuss how to target these mitochondrial defects in order to have beneficial effects as novel and complementary therapeutic avenues in neurodegenerative diseases. The critical evaluation of these strategies and their potential outcome can pave the way for finding novel therapies for neurodegenerative pathologies.
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Clay A, Hearle P, Schadt K, Lynch DR. New developments in pharmacotherapy for Friedreich ataxia. Expert Opin Pharmacother 2019; 20:1855-1867. [PMID: 31311349 DOI: 10.1080/14656566.2019.1639671] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Friedreich ataxia (FRDA), a rare disease caused by the deficiency of the mitochondrial matrix protein frataxin, affects roughly 1 in 50,000 individuals worldwide. Current and emerging therapies focus on reversing the deleterious effects of such deficiency including mitochondrial augmentation and increasing frataxin levels, providing the possibility of treatment options for this physiologically complex, multisystem disorder. Areas covered: In this review article, the authors discuss the current and prior in vivo and in vitro research studies related to the treatment of FRDA, with a particular interest in future implications of each therapy. Expert opinion: Since the discovery of FXN in 1996, multiple clinical trials have occurred or are currently occurring; at a rapid pace for a rare disease. These trials have been directed at the augmentation of mitochondrial function and/or alleviation of symptoms and are not regarded as potential cures in FRDA. Either a combination of therapies or a drug that replaces or increases the pathologically low levels of frataxin better represent potential cures in FRDA.
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Affiliation(s)
- Alexandra Clay
- Division of Neurology, Children's Hospital of Philadelphia , Philadelphia , PA , USA
| | - Patrick Hearle
- Division of Neurology, Children's Hospital of Philadelphia , Philadelphia , PA , USA
| | - Kim Schadt
- Division of Neurology, Children's Hospital of Philadelphia , Philadelphia , PA , USA
| | - David R Lynch
- Division of Neurology, Children's Hospital of Philadelphia , Philadelphia , PA , USA
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