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1
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Lu Y, Zhou J, Wang H, Gao H, Ning E, Shao Z, Hao Y, Yang X. Endoplasmic reticulum stress-mediated apoptosis and autophagy in osteoarthritis: From molecular mechanisms to therapeutic applications. Cell Stress Chaperones 2024; 29:805-830. [PMID: 39571722 DOI: 10.1016/j.cstres.2024.11.005] [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: 09/04/2024] [Revised: 11/08/2024] [Accepted: 11/16/2024] [Indexed: 12/09/2024] Open
Abstract
Osteoarthritis (OA) is characterized primarily by the degeneration of articular cartilage, with a high prevalence and disability rate. The functional phenotype of chondrocytes, as the sole cell type within cartilage, is vital for OA progression. Due to the avascular nature of cartilage and its limited regenerative capacity, repair following injury poses significant challenges. Various cellular stressors, including hypoxia, nutrient deprivation, oxidative stress, and collagen mutations, can lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), resulting in ER stress (ERS). In response to restore ER homeostasis as well as cellular vitality and function, a series of adaptive mechanisms are triggered, including the unfolded protein response, ER-associated degradation, and ER-phagy. Prolonged or severe ERS may exceed the adaptive capacity of cells, leading to dysregulation in apoptosis and autophagy-key pathogenic factors contributing to chondrocyte damage and OA progression. This review examines the relationship between ERS in OA chondrocytes and both apoptosis and autophagy in order to identify potential therapeutic targets and strategies for prevention and treatment of OA.
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Affiliation(s)
- Yifan Lu
- Orthopedics and Sports Medicine Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, PR China; Gusu School, Nanjing Medical University, Suzhou, PR China
| | - Jing Zhou
- Orthopedics and Sports Medicine Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, PR China; Gusu School, Nanjing Medical University, Suzhou, PR China
| | - Hong Wang
- Orthopedics and Sports Medicine Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, PR China; Gusu School, Nanjing Medical University, Suzhou, PR China
| | - Hua Gao
- Orthopedics and Sports Medicine Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, PR China; Gusu School, Nanjing Medical University, Suzhou, PR China
| | - Eryu Ning
- Gusu School, Nanjing Medical University, Suzhou, PR China; Department of Sports Rehabilitation, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, PR China
| | - Zhiqiang Shao
- Orthopedics and Sports Medicine Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, PR China; Gusu School, Nanjing Medical University, Suzhou, PR China
| | - Yuefeng Hao
- Orthopedics and Sports Medicine Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, PR China; Gusu School, Nanjing Medical University, Suzhou, PR China.
| | - Xing Yang
- Orthopedics and Sports Medicine Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, PR China; Gusu School, Nanjing Medical University, Suzhou, PR China.
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2
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Magno LAV, Pinto SHDB, Pacheco A, Rosa DVF, Gubert P, Romano-Silva MA. Stress survival and longevity of Caenorhabditis elegans lacking NCS-1. Toxicol Res (Camb) 2024; 13:tfae187. [PMID: 39555232 PMCID: PMC11567717 DOI: 10.1093/toxres/tfae187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 10/29/2024] [Accepted: 11/05/2024] [Indexed: 11/19/2024] Open
Abstract
Although dysfunctional Ca2+ signaling can trigger biochemical reactions that lead to cell death, the role of calcium-binding proteins (CBPs) in this process is still a topic of debate. Neuronal calcium sensor 1 (NCS-1) is a CBP that is highly conserved and has been shown to increase cell survival against various types of injuries. As such, we hypothesized that NCS-1 could also be a stress-responsive protein with potential effects on survival and longevity. To explore this possibility, we conducted experiments to examine how Caenorhabditis elegans ncs-1 mutant nematodes fared under three different stress conditions: hyperosmotic, thermal, and chemical oxidant challenges. Our results showed that while the lack of NCS-1 had no effect on survival responses to hyperosmotic and thermal stresses, ncs-1 worms demonstrated remarkable resistance to the oxidant paraquat in a dose-dependent manner. Based on these findings, we conclude that C. elegans may employ adaptive mechanisms in the absence of NCS-1 to survive specific oxidative stress stimuli.
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Affiliation(s)
- Luiz Alexandre Viana Magno
- Programa de Pós-Graduação em Ciências da Saúde (PPGCS), Faculdade Ciências Médicas de Minas Gerais (FCMMG), Alameda Ezequiel Dias, N° 275, Centro, 30130-110 Belo Horizonte, Minas Gerais, Brazil
- INCT em Neurotecnologia Responsável (INCT-NeurotecR), Avenida Alfredo Balena N° 190, Santa Efigênia, 30130-100, Belo Horizonte, Minas Gerais, Brazil
| | - Sofia Helena Dias Borges Pinto
- Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Avenida Alfredo Balena N° 190, Santa Efigênia, 30130-100, Belo Horizonte, Minas Gerais, Brazil
| | - Ailla Pacheco
- Programa de Pós-Graduação em Ciências da Saúde (PPGCS), Faculdade Ciências Médicas de Minas Gerais (FCMMG), Alameda Ezequiel Dias, N° 275, Centro, 30130-110 Belo Horizonte, Minas Gerais, Brazil
| | - Daniela Valadão Freitas Rosa
- INCT em Neurotecnologia Responsável (INCT-NeurotecR), Avenida Alfredo Balena N° 190, Santa Efigênia, 30130-100, Belo Horizonte, Minas Gerais, Brazil
- Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Avenida Alfredo Balena N° 190, Santa Efigênia, 30130-100, Belo Horizonte, Minas Gerais, Brazil
| | - Priscila Gubert
- Universidade Federal de Pernambuco (UFPE), Avenida Prof. Moraes Rego, Cidade Universitária, 50670-901, Recife, Pernambuco, Brazil
| | - Marco Aurélio Romano-Silva
- INCT em Neurotecnologia Responsável (INCT-NeurotecR), Avenida Alfredo Balena N° 190, Santa Efigênia, 30130-100, Belo Horizonte, Minas Gerais, Brazil
- Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Avenida Alfredo Balena N° 190, Santa Efigênia, 30130-100, Belo Horizonte, Minas Gerais, Brazil
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Lei Z, Niu J, Cai H, Kong Z, Ding X, Dong Y, Zhang D, Li X, Shao J, Lin A, Zhou R, Yang S, Yan Q. NF2 regulates IP3R-mediated Ca 2+ signal and apoptosis in meningiomas. FASEB J 2024; 38:e23737. [PMID: 38953724 DOI: 10.1096/fj.202400436r] [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: 02/27/2024] [Revised: 05/15/2024] [Accepted: 05/29/2024] [Indexed: 07/04/2024]
Abstract
Meningiomas are the most common primary intracranial tumors and account for nearly 30% of all nervous system tumors. Approximately half of meningioma patients exhibit neurofibromin 2 (NF2) gene inactivation. Here, NF2 was shown to interact with the endoplasmic reticulum (ER) calcium (Ca2+) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in IOMM-Lee, a high-grade malignant meningioma cell line, and the F1 subdomain of NF2 plays a critical role in this interaction. Functional assays indicated that NF2 promotes the phosphorylation of IP3R (Ser 1756) and IP3R-mediated endoplasmic reticulum (ER) Ca2+ release by binding to IP3R1, which results in Ca2+-dependent apoptosis. Knockout of NF2 decreased Ca2+ release and promoted resistance to apoptosis, which was rescued by wild-type NF2 overexpression but not by F1 subdomain deletion truncation overexpression. The effects of NF2 defects on the development of tumors were further studied in mouse models. The decreased expression level of NF2 caused by NF2 gene knockout or mutation affects the activity of the IP3R channel, which reduces Ca2+-dependent apoptosis, thereby promoting the development of tumors. We elucidated the interaction patterns of NF2 and IP3R1, revealed the molecular mechanism through which NF2 regulates IP3R1-mediated Ca2+ release, and elucidated the new pathogenic mechanism of meningioma-related NF2 variants. Our study broadens the current understanding of the biological function of NF2 and provides ideas for drug screening of NF2-associated meningioma.
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Affiliation(s)
- Zhaoying Lei
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jie Niu
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Huajian Cai
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhengyi Kong
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xue Ding
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yufei Dong
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Dong Zhang
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xu Li
- Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
| | - Jianzhong Shao
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Aifu Lin
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ruhong Zhou
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Shuxu Yang
- Department of Neurosurgery Sir Run Run Shaw Hospital, School of Medicine Zhejiang University, Hangzhou, Zhejiang, China
| | - Qingfeng Yan
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- Department of Pediatrics, The First Affiliated Hospital, School of Medicine Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang University, Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou, Zhejiang, China
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4
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Ge WD, Du TT, Wang CY, Sun LN, Wang YQ. Calcium signaling crosstalk between the endoplasmic reticulum and mitochondria, a new drug development strategies of kidney diseases. Biochem Pharmacol 2024; 225:116278. [PMID: 38740223 DOI: 10.1016/j.bcp.2024.116278] [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: 01/12/2024] [Revised: 04/25/2024] [Accepted: 05/10/2024] [Indexed: 05/16/2024]
Abstract
Calcium (Ca2+) acts as a second messenger and constitutes a complex and large information exchange system between the endoplasmic reticulum (ER) and mitochondria; this process is involved in various life activities, such as energy metabolism, cell proliferation and apoptosis. Increasing evidence has suggested that alterations in Ca2+ crosstalk between the ER and mitochondria, including alterations in ER and mitochondrial Ca2+ channels and related Ca2+ regulatory proteins, such as sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), inositol 1,4,5-trisphosphate receptor (IP3R), and calnexin (CNX), are closely associated with the development of kidney disease. Therapies targeting intracellular Ca2+ signaling have emerged as an emerging field in the treatment of renal diseases. In this review, we focused on recent advances in Ca2+ signaling, ER and mitochondrial Ca2+ monitoring methods and Ca2+ homeostasis in the development of renal diseases and sought to identify new targets and insights for the treatment of renal diseases by targeting Ca2+ channels or related Ca2+ regulatory proteins.
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Affiliation(s)
- Wen-Di Ge
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Department of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Tian-Tian Du
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Department of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Cao-Yang Wang
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Department of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Lu-Ning Sun
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Department of Pharmacy, Nanjing Medical University, Nanjing, China.
| | - Yong-Qing Wang
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Department of Pharmacy, Nanjing Medical University, Nanjing, China.
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5
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Zhou Y, Huang X, Jin Y, Qiu M, Ambe PC, Basharat Z, Hong W. The role of mitochondrial damage-associated molecular patterns in acute pancreatitis. Biomed Pharmacother 2024; 175:116690. [PMID: 38718519 DOI: 10.1016/j.biopha.2024.116690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/27/2024] [Accepted: 04/29/2024] [Indexed: 06/03/2024] Open
Abstract
Acute pancreatitis (AP) is one of the most common gastrointestinal tract diseases with significant morbidity and mortality. Current treatments remain unspecific and supportive due to the severity and clinical course of AP, which can fluctuate rapidly and unpredictably. Mitochondria, cellular power plant to produce energy, are involved in a variety of physiological or pathological activities in human body. There is a growing evidence indicating that mitochondria damage-associated molecular patterns (mtDAMPs) play an important role in pathogenesis and progression of AP. With the pro-inflammatory properties, released mtDAMPs may damage pancreatic cells by binding with receptors, activating downstream molecules and releasing inflammatory factors. This review focuses on the possible interaction between AP and mtDAMPs, which include cytochrome c (Cyt c), mitochondrial transcription factor A (TFAM), mitochondrial DNA (mtDNA), cardiolipin (CL), adenosine triphosphate (ATP) and succinate, with focus on experimental research and potential therapeutic targets in clinical practice. Preventing or diminishing the release of mtDAMPs or targeting the mtDAMPs receptors might have a role in AP progression.
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Affiliation(s)
- Yan Zhou
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China; School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Xiaoyi Huang
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China; School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Yinglu Jin
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China; School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Minhao Qiu
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Peter C Ambe
- Department of General Surgery, Visceral Surgery and Coloproctology, Vinzenz-Pallotti-Hospital Bensberg, Vinzenz-Pallotti-Str. 20-24, Bensberg 51429, Germany
| | | | - Wandong Hong
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
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6
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Wang J, Li P, Sun L, Zhang J, Yue K, Wang Y, Wu X. FAM83B regulates mitochondrial metabolism and anti-apoptotic activity in pulmonary adenocarcinoma. Apoptosis 2024; 29:743-756. [PMID: 38478170 DOI: 10.1007/s10495-024-01944-7] [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] [Accepted: 02/04/2024] [Indexed: 04/28/2024]
Abstract
Chemotherapy is an effective therapeutic modality; nevertheless, a significant proportion of patients diagnosed with lung adenocarcinoma (LUAD) demonstrate resistance to chemotherapy. Therefore, it is crucial to understand the potential regulatory mechanisms to develop novel treatment strategies. This study aims to understand how increased FAM83B expression impacts mitochondrial activity, cell apoptosis, and chemotherapy effectiveness in LUAD. Multiple assays, such as CCK8, wound healing, EdU, and transwell assays, were employed to confirm the augmented chemotherapy resistance, heightened cell proliferation, migration, and invasion caused by FAM83B overexpression in LUAD cells. Furthermore, MIMP, MTG, and ATP assays were utilized to quantify changes in mitochondrial metabolism. In vitro functional assays were performed to evaluate the influence of FAM83B overexpression on the malignant progression and resistance mechanisms to chemotherapy in LUAD. In the context of this study, it was determined that LUAD patients with increased FAM83B expression had shorter survival times, and tissue samples with FAM83B overexpression were more prone to metastasis compared to primary samples. As a result, FAM83B is identified as an adverse prognostic marker. The mechanistic analysis demonstrated that FAM83B impedes the translocation of calbindin 2 (CALB2) from the cytoplasm to the mitochondria, resulting in the inhibition of apoptosis and the promotion of mitochondrial activity. Consequently, this ultimately confers resistance to chemotherapy in LUAD. Furthermore, the administration of metformin, which blocks mitochondrial oxidative phosphorylation (OXPHOS), can restore sensitivity to drug resistance in LUAD. Taken together, these findings provide substantial evidence supporting the notion that FAM83B enhances chemotherapy resistance in LUAD through the upregulation of mitochondrial metabolism and the inhibition of apoptosis.
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Affiliation(s)
- Jiajia Wang
- Department of Pathology, School of Basic Medical Sciences and QiLu Hospital, Shandong University, Jinan, 250012, Shandong, China
| | - Panpan Li
- Department of Pathology, School of Basic Medical Sciences and QiLu Hospital, Shandong University, Jinan, 250012, Shandong, China
| | - Limin Sun
- Department of Orthopedics, Shandong Provincial Third Hospital, Jinan, 250031, Shandong, China
| | - Jing Zhang
- Department of Pathology, School of Basic Medical Sciences and QiLu Hospital, Shandong University, Jinan, 250012, Shandong, China
| | - Ke Yue
- Department of Pathology, School of Basic Medical Sciences and QiLu Hospital, Shandong University, Jinan, 250012, Shandong, China
| | - Yan Wang
- Department of Pathology, School of Basic Medical Sciences and QiLu Hospital, Shandong University, Jinan, 250012, Shandong, China
| | - Xiaojuan Wu
- Department of Pathology, School of Basic Medical Sciences and QiLu Hospital, Shandong University, Jinan, 250012, Shandong, China.
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Singh A, Tiwari S, Singh S. Pirh2 modulates the mitochondrial function and cytochrome c-mediated neuronal death during Alzheimer's disease. Cell Death Dis 2024; 15:331. [PMID: 38740775 PMCID: PMC11091053 DOI: 10.1038/s41419-024-06662-1] [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: 08/29/2022] [Revised: 03/26/2024] [Accepted: 04/09/2024] [Indexed: 05/16/2024]
Abstract
Pirh2 is an E3 ubiquitin ligase known to regulate the DNA damage responses through ubiquitylation of various participating signaling factors. DNA damage is a key pathological contributor to Alzheimer's disease (AD), therefore, the role of Pirh2 was investigated in streptozotocin and oligomer Aβ1-42 induced rodent experimental model of AD. Pirh2 protein abundance increased during AD conditions, and transient silencing of Pirh2 inhibited the disease-specific pathological markers like level of p-Tau, βamyloid, acetylcholinesterase activity, and neuronal death. Biochemically, Pirh2 silencing significantly attenuated the oxidative stress, depleted mitochondrial membrane potential, cytochrome c translocation from mitochondria to cytosol, and depleted mitochondrial complex-I activity, and ATP level. Pirh2 silencing also inhibited the altered level of VDAC1, hsp75, hexokinase1, t-Bid, caspase-9, and altered level of apoptotic proteins (Bcl-2, Bax). MALDI-TOF/TOF, co-immunoprecipitation, and UbcH13-linked ubiquitylation assay confirmed the interaction of Pirh2 with cytochrome c and the role of Pirh2 in ubiquitylation of cytochrome c, along with Pirh2-dependent altered proteasome activity. Additionally, Pirh2 silencing further inhibited the translocation of mitochondrion-specific endonuclease G and apoptosis-inducing factors to the nucleus and DNA damage. In conclusion, findings suggested the significant implication of Pirh2 in disease pathogenesis, particularly through impaired mitochondrial function, including biochemical alterations, translocation of cytochrome c, endonuclease G and apoptosis-inducing factor, DNA damage, and neuronal apoptosis.
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Affiliation(s)
- Abhishek Singh
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Shubhangini Tiwari
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Sarika Singh
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, India.
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8
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Zhou Z, Arroum T, Luo X, Kang R, Lee YJ, Tang D, Hüttemann M, Song X. Diverse functions of cytochrome c in cell death and disease. Cell Death Differ 2024; 31:387-404. [PMID: 38521844 PMCID: PMC11043370 DOI: 10.1038/s41418-024-01284-8] [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: 10/07/2023] [Revised: 03/13/2024] [Accepted: 03/18/2024] [Indexed: 03/25/2024] Open
Abstract
The redox-active protein cytochrome c is a highly positively charged hemoglobin that regulates cell fate decisions of life and death. Under normal physiological conditions, cytochrome c is localized in the mitochondrial intermembrane space, and its distribution can extend to the cytosol, nucleus, and extracellular space under specific pathological or stress-induced conditions. In the mitochondria, cytochrome c acts as an electron carrier in the electron transport chain, facilitating adenosine triphosphate synthesis, regulating cardiolipin peroxidation, and influencing reactive oxygen species dynamics. Upon cellular stress, it can be released into the cytosol, where it interacts with apoptotic peptidase activator 1 (APAF1) to form the apoptosome, initiating caspase-dependent apoptotic cell death. Additionally, following exposure to pro-apoptotic compounds, cytochrome c contributes to the survival of drug-tolerant persister cells. When translocated to the nucleus, it can induce chromatin condensation and disrupt nucleosome assembly. Upon its release into the extracellular space, cytochrome c may act as an immune mediator during cell death processes, highlighting its multifaceted role in cellular biology. In this review, we explore the diverse structural and functional aspects of cytochrome c in physiological and pathological responses. We summarize how posttranslational modifications of cytochrome c (e.g., phosphorylation, acetylation, tyrosine nitration, and oxidation), binding proteins (e.g., HIGD1A, CHCHD2, ITPR1, and nucleophosmin), and mutations (e.g., G41S, Y48H, and A51V) affect its function. Furthermore, we provide an overview of the latest advanced technologies utilized for detecting cytochrome c, along with potential therapeutic approaches related to this protein. These strategies hold tremendous promise in personalized health care, presenting opportunities for targeted interventions in a wide range of conditions, including neurodegenerative disorders, cardiovascular diseases, and cancer.
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Affiliation(s)
- Zhuan Zhou
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Tasnim Arroum
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA
| | - Xu Luo
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Yong J Lee
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
| | - Maik Hüttemann
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI, 48201, USA.
| | - Xinxin Song
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
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9
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Gao W, Liu YF, Zhang YX, Wang Y, Jin YQ, Yuan H, Liang XY, Ji XY, Jiang QY, Wu DD. The potential role of hydrogen sulfide in cancer cell apoptosis. Cell Death Discov 2024; 10:114. [PMID: 38448410 PMCID: PMC10917771 DOI: 10.1038/s41420-024-01868-w] [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: 07/12/2023] [Revised: 02/05/2024] [Accepted: 02/14/2024] [Indexed: 03/08/2024] Open
Abstract
For a long time, hydrogen sulfide (H2S) has been considered a toxic compound, but recent studies have found that H2S is the third gaseous signaling molecule which plays a vital role in physiological and pathological conditions. Currently, a large number of studies have shown that H2S mediates apoptosis through multiple signaling pathways to participate in cancer occurrence and development, for example, PI3K/Akt/mTOR and MAPK signaling pathways. Therefore, the regulation of the production and metabolism of H2S to mediate the apoptotic process of cancer cells may improve the effectiveness of cancer treatment. In this review, the role and mechanism of H2S in cancer cell apoptosis in mammals are summarized.
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Affiliation(s)
- Wei Gao
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Ya-Fang Liu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Yan-Xia Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Yan Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Yu-Qing Jin
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Hang Yuan
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Xiao-Yi Liang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Xin-Ying Ji
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China.
- Faculty of Basic Medical Subjects, Shu-Qing Medical College of Zhengzhou, Zhengzhou, Henan, 450064, China.
| | - Qi-Ying Jiang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China.
| | - Dong-Dong Wu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China.
- School of Stomatology, Henan University, Kaifeng, Henan, 475004, China.
- Department of Stomatology, Huaihe Hospital of Henan University, Kaifeng, Henan, 475000, China.
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Singh R, Kaur N, Choubey V, Dhingra N, Kaur T. Endoplasmic reticulum stress and its role in various neurodegenerative diseases. Brain Res 2024; 1826:148742. [PMID: 38159591 DOI: 10.1016/j.brainres.2023.148742] [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: 08/18/2023] [Revised: 12/07/2023] [Accepted: 12/24/2023] [Indexed: 01/03/2024]
Abstract
The Endoplasmic reticulum (ER), a critical cellular organelle, maintains cellular homeostasis by regulating calcium levels and orchestrating essential functions such as protein synthesis, folding, and lipid production. A pivotal aspect of ER function is its role in protein quality control. When misfolded proteins accumulate within the ER due to factors like protein folding chaperone dysfunction, toxicity, oxidative stress, or inflammation, it triggers the Unfolded protein response (UPR). The UPR involves the activation of chaperones like calnexin, calreticulin, glucose-regulating protein 78 (GRP78), and Glucose-regulating protein 94 (GRP94), along with oxidoreductases like protein disulphide isomerases (PDIs). Cells employ the Endoplasmic reticulum-associated degradation (ERAD) mechanism to counteract protein misfolding. ERAD disruption causes the detachment of GRP78 from transmembrane proteins, initiating a cascade involving Inositol-requiring kinase/endoribonuclease 1 (IRE1), Activating transcription factor 6 (ATF6), and Protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathways. The accumulation and deposition of misfolded proteins within the cell are hallmarks of numerous neurodegenerative diseases. These aberrant proteins disrupt normal neuronal signalling and contribute to impaired cellular homeostasis, including oxidative stress and compromised protein degradation pathways. In essence, ER stress is defined as the cellular response to the accumulation of misfolded proteins in the endoplasmic reticulum, encompassing a series of signalling pathways and molecular events that aim to restore cellular homeostasis. This comprehensive review explores ER stress and its profound implications for the pathogenesis and progression of neurodegenerative diseases.
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Affiliation(s)
- Rimaljot Singh
- Department of Biophysics, Panjab University Chandigarh, India
| | - Navpreet Kaur
- Department of Biophysics, Panjab University Chandigarh, India
| | - Vinay Choubey
- Department of Pharmacology, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Neelima Dhingra
- University Institute of Pharmaceutical Sciences, Panjab University Chandigarh, India
| | - Tanzeer Kaur
- Department of Biophysics, Panjab University Chandigarh, India.
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11
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Wu L, Chen J. Type 3 IP3 receptor: Its structure, functions, and related disease implications. Channels (Austin) 2023; 17:2267416. [PMID: 37818548 PMCID: PMC10569359 DOI: 10.1080/19336950.2023.2267416] [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: 05/21/2023] [Accepted: 10/02/2023] [Indexed: 10/12/2023] Open
Abstract
Cell-fate decisions depend on the precise and strict regulation of multiple signaling molecules and transcription factors, especially intracellular Ca2+ homeostasis and dynamics. Type 3 inositol 1,4,5-triphosphate receptor (IP3R3) is an a tetrameric channel that can mediate the release of Ca2+ from the endoplasmic reticulum (ER) in response to extracellular stimuli. The gating of IP3R3 is regulated not only by ligands but also by other interacting proteins. To date, extensive research conducted on the basic structure of IP3R3, as well as its regulation by ligands and interacting proteins, has provided novel perspectives on its biological functions and pathogenic mechanisms. This review aims to discuss recent advancements in the study of IP3R3 and provides a comprehensive overview of the relevant literature pertaining to its structure, biological functions, and pathogenic mechanisms.
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Affiliation(s)
- Lvying Wu
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Jin Chen
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
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12
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Sammeta SS, Banarase TA, Rahangdale SR, Wankhede NL, Aglawe MM, Taksande BG, Mangrulkar SV, Upaganlawar AB, Koppula S, Kopalli SR, Umekar MJ, Kale MB. Molecular understanding of ER-MT communication dysfunction during neurodegeneration. Mitochondrion 2023; 72:59-71. [PMID: 37495165 DOI: 10.1016/j.mito.2023.07.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 07/13/2023] [Accepted: 07/23/2023] [Indexed: 07/28/2023]
Abstract
Biological researchers are seeing organelles in a new light. These cellular entities have been believed to be singular and distinctive structures that performed specialized purposes for a very long time. But in recentpast years, scientists have learned that organelles become dynamic and make physical contact. Additionally, Biological processes are regulated by organelles interactions and its alteration play an important role in cell malfunctioning and several pathologies, including neurodegenerative diseases. Mitochondrial-ER contact sites (MERCS) have received considerable attention in the domain of cell homeostasis and dysfunction, specifically in the area of neurodegeneration. This is largely due to the significant role of this subcellular compartment in a diverse array of vital cellular functions, including Ca2+ homeostasis, transport, bioenergetics and turnover, mitochondrial dynamics, apoptotic signaling, ER stress, and inflammation. A significant number of disease-associated proteins were found to physically interact with the ER-Mitochondria (ER-MT) interface, causing structural and/or functional alterations in this compartment. In this review, we summarize current knowledge about the structure and functions of the ER-MT contact sites, as well as the possible repercussions of their alteration in notable neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and fronto-temporal dementia. The constraints and complexities in defining the nature and origin of the highlighted defects in ER-MT communication, as well as their concise contribution to the neurodegenerative process, are illustrated in particular. The possibility of using MERCS as a potential drug target to prevent neuronal damage and ultimately neurodegeneration is the topic of our final discussion.
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Affiliation(s)
- Shivkumar S Sammeta
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Trupti A Banarase
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Sandip R Rahangdale
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Nitu L Wankhede
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Manish M Aglawe
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Brijesh G Taksande
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Shubhada V Mangrulkar
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Aman B Upaganlawar
- SNJB's Shriman Sureshdada Jain College of Pharmacy, Neminagar, Chandwad, Nashik, Maharashtra, India
| | - Sushruta Koppula
- College of Biomedical and Health Sciences, Konkuk University, Chungju-Si, Chungcheongbuk Do 27478, Republic of Korea
| | - Spandana Rajendra Kopalli
- Department of Bioscience and Biotechnology, Sejong University, Gwangjin-gu, Seoul 05006, Republic of Korea
| | - Milind J Umekar
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Mayur B Kale
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India.
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13
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Gebert M, Sławski J, Kalinowski L, Collawn JF, Bartoszewski R. The Unfolded Protein Response: A Double-Edged Sword for Brain Health. Antioxidants (Basel) 2023; 12:1648. [PMID: 37627643 PMCID: PMC10451475 DOI: 10.3390/antiox12081648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/14/2023] [Accepted: 08/19/2023] [Indexed: 08/27/2023] Open
Abstract
Efficient brain function requires as much as 20% of the total oxygen intake to support normal neuronal cell function. This level of oxygen usage, however, leads to the generation of free radicals, and thus can lead to oxidative stress and potentially to age-related cognitive decay and even neurodegenerative diseases. The regulation of this system requires a complex monitoring network to maintain proper oxygen homeostasis. Furthermore, the high content of mitochondria in the brain has elevated glucose demands, and thus requires a normal redox balance. Maintaining this is mediated by adaptive stress response pathways that permit cells to survive oxidative stress and to minimize cellular damage. These stress pathways rely on the proper function of the endoplasmic reticulum (ER) and the activation of the unfolded protein response (UPR), a cellular pathway responsible for normal ER function and cell survival. Interestingly, the UPR has two opposing signaling pathways, one that promotes cell survival and one that induces apoptosis. In this narrative review, we discuss the opposing roles of the UPR signaling pathways and how a better understanding of these stress pathways could potentially allow for the development of effective strategies to prevent age-related cognitive decay as well as treat neurodegenerative diseases.
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Affiliation(s)
- Magdalena Gebert
- Department of Medical Laboratory Diagnostics—Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, 80-134 Gdansk, Poland
| | - Jakub Sławski
- Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, F. Joliot-Curie 14a Street, 50-383 Wroclaw, Poland
| | - Leszek Kalinowski
- Department of Medical Laboratory Diagnostics—Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, 80-134 Gdansk, Poland
- BioTechMed Centre, Department of Mechanics of Materials and Structures, Gdansk University of Technology, 11/12 Narutowicza Street, 80-233 Gdansk, Poland
| | - James F. Collawn
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Rafal Bartoszewski
- Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, F. Joliot-Curie 14a Street, 50-383 Wroclaw, Poland
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14
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Semenova MA, Chertkova RV, Kirpichnikov MP, Dolgikh DA. Molecular Interactions between Neuroglobin and Cytochrome c: Possible Mechanisms of Antiapoptotic Defense in Neuronal Cells. Biomolecules 2023; 13:1233. [PMID: 37627298 PMCID: PMC10452090 DOI: 10.3390/biom13081233] [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: 06/22/2023] [Revised: 08/06/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Neuroglobin, which is a heme protein from the globin family that is predominantly expressed in nervous tissue, can promote a neuronal survivor. However, the molecular mechanisms underlying the neuroprotective function of Ngb remain poorly understood to this day. The interactions between neuroglobin and mitochondrial cytochrome c may serve as at least one of the mechanisms of neuroglobin-mediated neuroprotection. Interestingly, neuroglobin and cytochrome c possibly can interact with or without electron transfer both in the cytoplasm and within the mitochondria. This review provides a general picture of molecular interactions between neuroglobin and cytochrome c based on the recent experimental and computational work on neuroglobin and cytochrome c interactions.
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Affiliation(s)
- Marina A. Semenova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho–Maklaya St. 16/10, 117997 Moscow, Russia
| | - Rita V. Chertkova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho–Maklaya St. 16/10, 117997 Moscow, Russia
| | - Mikhail P. Kirpichnikov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho–Maklaya St. 16/10, 117997 Moscow, Russia
- Biology Department, Lomonosov Moscow State University, Leninskie Gory, 119899 Moscow, Russia
| | - Dmitry A. Dolgikh
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho–Maklaya St. 16/10, 117997 Moscow, Russia
- Biology Department, Lomonosov Moscow State University, Leninskie Gory, 119899 Moscow, Russia
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15
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Kushwaha AD, Kalra N, Varshney R, Saraswat D. Mitochondrial Ca 2+ overload due to altered proteostasis amplifies apoptosis in C2C12 myoblasts under hypoxia: Protective role of nanocurcumin formulation. IUBMB Life 2023; 75:673-687. [PMID: 37002613 DOI: 10.1002/iub.2720] [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: 12/20/2022] [Accepted: 02/04/2023] [Indexed: 07/21/2023]
Abstract
Severe hypoxia triggers apoptosis leads to myofibers loss and is attributable to impaired intracellular calcium (iCa2+ ) homeostasis, resulting in reduced muscle activity. Hypoxia increases intracellular Ca2+ by activating the release of Ca2+ from iCa2+ stores, however, the effect of increased [iCa2+ ] on the mitochondria of muscle cells at high-altitude hypoxia is largely unexplored. This study examined mitochondrial Ca2+ overload due to altered expression of mitochondrial calcium uptake 1 (MICU1), that is, a gatekeeper of the mitochondrial Ca2+ uniporter, impaired mitochondrial membrane potential (ΔΨm). p53 stabilization and its translocation to the mitochondria were observed following disrupted mitochondrial membrane integrity in myoblasts under hypoxia. Furthermore, the downstream effects of p53 led to the upregulation of proapoptotic proteins (Bax, Caspase-3, and cytochrome C) in myoblasts under hypoxia. Nanocurcumin-pyrroloquinoline quinone formulation (NCF; Indian patent no. 302877), developed to address hypoxia-induced consequences, was found to be beneficial in maintaining mitochondrial Ca2+ homeostasis and limiting p53 translocation into mitochondria under hypoxia in muscle myoblasts. NCF treatment also modulates heat shock proteins and apoptosis-regulating protein expression in myoblasts. Conclusively, we proposed that mitochondrial Ca2+ overload due to altered MICU1 expression intensifies apoptosis and mitochondrial dysfunctionality. The study also reported that NCF could improve mitochondrial [Ca2+ ] homeostasis and antiapoptotic ability in C2C12 myoblasts under hypoxia.
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Affiliation(s)
- Asha D Kushwaha
- Defense Institute of Physiology and Allied Sciences, Defense Research and Development Organization (DRDO), Delhi, India
| | - Namita Kalra
- Institute of Nuclear Medicine and Allied Sciences, Defense Research and Development Organization (DRDO), Delhi, India
| | - Rajeev Varshney
- Defense Institute of Physiology and Allied Sciences, Defense Research and Development Organization (DRDO), Delhi, India
| | - Deepika Saraswat
- Defense Institute of Physiology and Allied Sciences, Defense Research and Development Organization (DRDO), Delhi, India
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16
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Thompson W, Papoutsakis ET. The role of biomechanical stress in extracellular vesicle formation, composition and activity. Biotechnol Adv 2023; 66:108158. [PMID: 37105240 DOI: 10.1016/j.biotechadv.2023.108158] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/23/2023] [Accepted: 04/24/2023] [Indexed: 04/29/2023]
Abstract
Extracellular vesicles (EVs) are cornerstones of intercellular communication with exciting fundamental, clinical, and more broadly biotechnological applications. However, variability in EV composition, which results from the culture conditions used to generate the EVs, poses significant fundamental and applied challenges and a hurdle for scalable bioprocessing. Thus, an understanding of the relationship between EV production (and for clinical applications, manufacturing) and EV composition is increasingly recognized as important and necessary. While chemical stimulation and culture conditions such as cell density are known to influence EV biology, the impact of biomechanical forces on the generation, properties, and biological activity of EVs remains poorly understood. Given the omnipresence of these forces in EV preparation and in biomanufacturing, expanding the understanding of their impact on EV composition-and thus, activity-is vital. Although several publications have examined EV preparation and bioprocessing and briefly discussed biomechanical stresses as variables of interest, this review represents the first comprehensive evaluation of the impact of such stresses on EV production, composition and biological activity. We review how EV biogenesis, cargo, efficacy, and uptake are uniquely affected by various types, magnitudes, and durations of biomechanical forces, identifying trends that emerge both generically and for individual cell types. We also describe implications for scalable bioprocessing, evaluating processes inherent in common EV production and isolation methods, and propose a path forward for rigorous EV quality control.
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Affiliation(s)
- Will Thompson
- Department of Chemical and Biomolecular Engineering, University of Delaware, 590 Avenue 1743, Newark, DE 19713, USA
| | - Eleftherios Terry Papoutsakis
- Department of Chemical and Biomolecular Engineering, University of Delaware, 590 Avenue 1743, Newark, DE 19713, USA.
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17
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Wang G, Fan F, Sun C, Hu Y. Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma? Cancers (Basel) 2022; 14:5340. [PMID: 36358759 PMCID: PMC9654020 DOI: 10.3390/cancers14215340] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/21/2022] [Accepted: 10/27/2022] [Indexed: 09/22/2023] Open
Abstract
Multiple myeloma (MM) is the second most common hematologic malignancy, resulting from the clonal proliferation of malignant plasma cells within the bone marrow. Despite significant advances that have been made with novel drugs over the past two decades, MM patients often develop therapy resistance, especially to bortezomib, the first-in-class proteasome inhibitor that was approved for treatment of MM. As highly secretory monoclonal protein-producing cells, MM cells are characterized by uploaded endoplasmic reticulum stress (ERS), and rely heavily on the ERS response for survival. Great efforts have been made to illustrate how MM cells adapt to therapeutic stresses through modulating the ERS response. In this review, we summarize current knowledge on the mechanisms by which ERS response pathways influence MM cell fate and response to treatment. Moreover, based on promising results obtained in preclinical studies, we discuss the prospect of applying ERS modulators to overcome drug resistance in MM.
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Affiliation(s)
- Guangqi Wang
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan 430022, China
| | - Fengjuan Fan
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan 430022, China
| | - Chunyan Sun
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan 430022, China
- Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Yu Hu
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan 430022, China
- Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan 430074, China
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18
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Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease. Int J Mol Sci 2022; 23:ijms232113043. [PMID: 36361826 PMCID: PMC9657547 DOI: 10.3390/ijms232113043] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 10/16/2022] [Accepted: 10/25/2022] [Indexed: 11/23/2022] Open
Abstract
An increasing number of the population all around the world suffer from age-associated neurodegenerative diseases including Parkinson’s disease (PD). This disorder presents different signs of genetic, epigenetic and environmental origin, and molecular, cellular and intracellular dysfunction. At the molecular level, α-synuclein (αSyn) was identified as the principal molecule constituting the Lewy bodies (LB). The gut microbiota participates in the pathogenesis of PD and may contribute to the loss of dopaminergic neurons through mitochondrial dysfunction. The most important pathogenetic link is an imbalance of Ca2+ ions, which is associated with redox imbalance in the cells and increased generation of reactive oxygen species (ROS). In this review, genetic, epigenetic and environmental factors that cause these disorders and their cause-and-effect relationships are considered. As a constituent of environmental factors, the example of organophosphates (OPs) is also reviewed. The role of endothelial damage in the pathogenesis of PD is discussed, and a ‘triple hit hypothesis’ is proposed as a modification of Braak’s dual hit one. In the absence of effective therapies for neurodegenerative diseases, more and more evidence is emerging about the positive impact of nutritional structure and healthy lifestyle on the state of blood vessels and the risk of developing these diseases.
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19
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Rosa N, Speelman-Rooms F, Parys JB, Bultynck G. Modulation of Ca 2+ signaling by antiapoptotic Bcl-2 versus Bcl-xL: From molecular mechanisms to relevance for cancer cell survival. Biochim Biophys Acta Rev Cancer 2022; 1877:188791. [PMID: 36162541 DOI: 10.1016/j.bbcan.2022.188791] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 08/29/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022]
Abstract
Members of the Bcl-2-protein family are key controllers of apoptotic cell death. The family is divided into antiapoptotic (including Bcl-2 itself, Bcl-xL, Mcl-1, etc.) and proapoptotic members (Bax, Bak, Bim, Bim, Puma, Noxa, Bad, etc.). These proteins are well known for their canonical role in the mitochondria, where they control mitochondrial outer membrane permeabilization and subsequent apoptosis. However, several proteins are recognized as modulators of intracellular Ca2+ signals that originate from the endoplasmic reticulum (ER), the major intracellular Ca2+-storage organelle. More than 25 years ago, Bcl-2, the founding member of the family, was reported to control apoptosis through Ca2+ signaling. Further work elucidated that Bcl-2 directly targets and inhibits inositol 1,4,5-trisphosphate receptors (IP3Rs), thereby suppressing proapoptotic Ca2+ signaling. In addition to Bcl-2, Bcl-xL was also shown to impact cell survival by sensitizing IP3R function, thereby promoting prosurvival oscillatory Ca2+ release. However, new work challenges this model and demonstrates that Bcl-2 and Bcl-xL can both function as inhibitors of IP3Rs. This suggests that, depending on the cell context, Bcl-xL could support very distinct Ca2+ patterns. This not only raises several questions but also opens new possibilities for the treatment of Bcl-xL-dependent cancers. In this review, we will discuss the similarities and divergences between Bcl-2 and Bcl-xL regarding Ca2+ homeostasis and IP3R modulation from both a molecular and a functional point of view, with particular emphasis on cancer cell death resistance mechanisms.
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Affiliation(s)
- Nicolas Rosa
- KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium
| | - Femke Speelman-Rooms
- KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium
| | - Jan B Parys
- KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium
| | - Geert Bultynck
- KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium.
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20
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Morin attenuates neurobehavioural deficits, hippocampal oxidative stress, inflammation, and apoptosis in rats co-exposed to bisphenol S and diethyl phthalate. Brain Res 2022; 1794:148068. [PMID: 36041494 DOI: 10.1016/j.brainres.2022.148068] [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: 05/14/2022] [Revised: 08/17/2022] [Accepted: 08/24/2022] [Indexed: 11/23/2022]
Abstract
Endocrine-disrupting pollutants (EDPs) remain pervasive in the environment. Bisphenol S (BPS) and diethyl phthalates (DEP) are commonly used to replace the more toxic EDPs. However, it is unclear if they induce neurotoxicity, like their predecessors. Morin possesses relevant neuro-pharmacological activities. Hence, we sought to evaluate the protective effects of morin against the neurotoxic effects previously reported for EDPs. Male Wistar rats were exposed to a mixture of BPS and DEP (MBD) and treated with morin for 21 days. Behavioural assessments were conducted, and the hippocampal tissues were processed for analysis. Rats exposed to MBD presented anxiety-like behaviours, impaired cognitive and motor functions compared to the control group. MBD exposure induced hyperactivity of neurosignalling enzymes (AChE, ADA, MAO-A) and depleted hippocampal antioxidants (SOD, CAT, GPx, and GSH). MBD exposure increased calcium levels and inhibited total Ca2+-ATPase activity. Levels of reactive species (NO and H2O2) and oxidative damage markers (MDA and AOPP) were significantly (P < 0.05) elevated compared to control. The hippocampal expressions of IL-1β, TNFα, BAX, and APAF-1 in the MBD-exposed rats were significantly higher compared to control. Correspondingly, NF-κB and caspase-3 pathways were activated in the hippocampus of MBD-exposed rats, while the expressions of IL-10 and BDNF were repressed. However, co-treatment with morin improved the neurobehavioral outcomes, alleviated the hyperactivity of neurosignalling enzymes, while suppressing hippocampal oxidative stress, inflammation, and apoptosis. Histological and stereological evaluations supported these findings. In conclusion, co-exposure to BPS and DEP elicit similar neurotoxic outcomes as their predecessors, while morin confers marked protection against these outcomes.
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21
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Hakiminia B, Alikiaii B, Khorvash F, Mousavi S. Oxidative stress and mitochondrial dysfunction following traumatic brain injury: From mechanistic view to targeted therapeutic opportunities. Fundam Clin Pharmacol 2022; 36:612-662. [PMID: 35118714 DOI: 10.1111/fcp.12767] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 01/15/2022] [Accepted: 02/02/2022] [Indexed: 02/07/2023]
Abstract
Traumatic brain injury (TBI) is one of the most prevalent causes of permanent physical and cognitive disabilities. TBI pathology results from primary insults and a multi-mechanistic biochemical process, termed as secondary brain injury. Currently, there are no pharmacological agents for definitive treatment of patients with TBI. This article is presented with the purpose of reviewing molecular mechanisms of TBI pathology, as well as potential strategies and agents against pathological pathways. In this review article, materials were obtained by searching PubMed, Scopus, Elsevier, Web of Science, and Google Scholar. This search was considered without time limitation. Evidence indicates that oxidative stress and mitochondrial dysfunction are two key mediators of the secondary injury cascade in TBI pathology. TBI-induced oxidative damage results in the structural and functional impairments of cellular and subcellular components, such as mitochondria. Impairments of mitochondrial electron transfer chain and mitochondrial membrane potential result in a vicious cycle of free radical formation and cell apoptosis. The results of some preclinical and clinical studies, evaluating mitochondria-targeted therapies, such as mitochondria-targeted antioxidants and compounds with pleiotropic effects after TBI, are promising. As a proposed strategy in recent years, mitochondria-targeted multipotential therapy is a new hope, waiting to be confirmed. Moreover, based on the available findings, biologics, such as stem cell-based therapy and transplantation of mitochondria are novel potential strategies for the treatment of TBI; however, more studies are needed to clearly confirm the safety and efficacy of these strategies.
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Affiliation(s)
- Bahareh Hakiminia
- Department of Clinical Pharmacy and Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Babak Alikiaii
- Department of Anesthesiology and Intensive Care, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fariborz Khorvash
- Department of Neurology, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sarah Mousavi
- Department of Clinical Pharmacy and Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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22
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Jarius S, Bräuninger S, Chung HY, Geis C, Haas J, Komorowski L, Wildemann B, Roth C. Inositol 1,4,5-trisphosphate receptor type 1 autoantibody (ITPR1-IgG/anti-Sj)-associated autoimmune cerebellar ataxia, encephalitis and peripheral neuropathy: review of the literature. J Neuroinflammation 2022; 19:196. [PMID: 35907972 PMCID: PMC9338677 DOI: 10.1186/s12974-022-02545-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 06/23/2022] [Indexed: 11/10/2022] Open
Abstract
Background In 2014, we first described novel autoantibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1-IgG/anti-Sj) in patients with autoimmune cerebellar ataxia (ACA) in this journal. Here, we provide a review of the available literature on ITPR1-IgG/anti-Sj, covering clinical and paraclinical presentation, tumour association, serological findings, and immunopathogenesis. Methods Review of the peer-reviewed and PubMed-listed English language literature on ITPR1-IgG/anti-Sj. In addition, we provide an illustrative report on a new patient with ITPR1-IgG-associated encephalitis with cognitive decline and psychosis. Results So far, at least 31 patients with serum ITPR1-IgG/anti-Sj have been identified (clinical information available for 21). The most common manifestations were ACA, encephalopathy with seizures, myelopathy, and (radiculo)neuropathy, including autonomic neuropathy. In 45% of cases, an underlying tumour was present, making the condition a facultative paraneoplastic neurological disorder. The neurological syndrome preceded tumour diagnosis in all but one case. In most cases, immunotherapy had only moderate or no effect. The association of ITPR1-IgG/anti-Sj with manifestations other than ACA is corroborated by the case of a 48-year-old woman with high-titre ITPR1-IgG/anti-Sj antibodies and rapid cognitive decline, affecting memory, attention and executive function, and psychotic manifestations, including hallucinations, investigated here in detail. FDG-PET revealed right-temporal glucose hypermetabolism compatible with limbic encephalitis. Interestingly, ITPR1-IgG/anti-Sj mainly belonged to the IgG2 subclass in both serum and cerebrospinal fluid (CSF) in this and further patients, while it was predominantly IgG1 in other patients, including those with more severe outcome, and remained detectable over the entire course of disease. Immunotherapy with intravenous methylprednisolone, plasma exchange, and intravenous immunoglobulins, was repeatedly followed by partial or complete recovery. Long-term treatment with cyclophosphamide was paralleled by relative stabilization, although the patient noted clinical worsening at the end of each treatment cycle. Conclusions The spectrum of neurological manifestations associated with ITPR1 autoimmunity is broader than initially thought. Immunotherapy may be effective in some cases. Studies evaluating the frequency of ITPR1-IgG/anti-Sj in patients with cognitive decline and/or psychosis of unknown aetiology are warranted. Tumour screening is essential in patients presenting with ITPR1-IgG/anti-Sj.
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Affiliation(s)
- Sven Jarius
- Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany.
| | | | - Ha-Yeun Chung
- Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany
| | - Christian Geis
- Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany
| | - Jürgen Haas
- Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany
| | - Lars Komorowski
- Institute for Experimental Immunology, affiliated to EUROIMMUN Medizinische Labordiagnostika AG, Lübeck, Germany
| | - Brigitte Wildemann
- Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany
| | - Christian Roth
- Department of Neurology, DRK-Kliniken Nordhessen, Kassel, Germany.
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Yu D, Feng Y, Jiang Z, Yan T, Fang K, Shi Y, Zhang J, Zhang S. The role of human antigen R (HuR) in modulating proliferation, senescence and radiosensitivity of skin cells. Exp Ther Med 2022; 24:566. [PMID: 35965840 PMCID: PMC9372994 DOI: 10.3892/etm.2022.11503] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 06/22/2022] [Indexed: 11/19/2022] Open
Abstract
The skin is the largest outermost organ of the human body. It is vulnerable to various damages, such as ionizing radiation. Exploration of proliferation, senescence and radiosensitivity of skin cells contributes to the development of medical and cosmetic countermeasures against skin aging and toward injury protection. Human antigen R (HuR) is one of the most widely studied RNA-binding proteins and serves an important role in stabilization of mRNA and regulation of the expression of the target genes. To investigate the role of HuR in modulating proliferation, senescence and radiosensitivity of skin cells, the present study performed an in vitro study using lentivirus-mediated overexpression or silencing of HuR in human keratinocyte HaCaT cells and human skin fibroblast WS1 cells. The results indicated that overexpression of HuR promoted proliferation, whereas downregulation of HuR inhibited proliferation of HaCaT and WS1 cells. Overexpression of HuR reduced apoptosis and senescence in skin cells. RNA-Seq of skin cells with HuR overexpression or knockdown identified 77 mRNAs positively or negatively correlated with HuR expression levels. In addition, silencing of HuR induced a significant increase in radiogenic reactive oxygen species after irradiation. Overexpression of HuR increased radiotolerance of HaCaT and WS1 cells. RNA immunoprecipitation coupled with RNA-Seq identified 14 mRNAs interacting with HuR upon radiation exposure. Overall, the findings of the present study illustrated the key role of HuR in modulating proliferation, senescence and radiosensitivity of skin cells providing a new therapeutic strategy for cosmetic treatments and to combat skin injury.
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Affiliation(s)
- Daojiang Yu
- Department of Surgery, Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610051, P.R. China
| | - Yahui Feng
- Department of Surgery, Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610051, P.R. China
| | - Zhiqiang Jiang
- Department of Surgery, Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610051, P.R. China
| | - Tao Yan
- Department of Surgery, Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610051, P.R. China
| | - Kai Fang
- Department of Surgery, Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610051, P.R. China
| | - Yuhong Shi
- Department of Surgery, Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610051, P.R. China
| | - Jie Zhang
- Radiation Medicine Department of Institute of Preventive Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Shuyu Zhang
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Chengdu, Sichuan 610041, P.R. China
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24
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He W, Huang L, Luo H, Chen J, Li W, Zhang Y, An Y, Zhang W. The Positive and Negative Effects of Calcium Supplementation on Mortality in Septic ICU Patients Depend on Disease Severity: A Retrospective Study from the MIMIC-III. Crit Care Res Pract 2022; 2022:2520695. [PMID: 35782335 PMCID: PMC9242801 DOI: 10.1155/2022/2520695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 12/17/2021] [Accepted: 05/17/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Calcium administration in septic patients with hypocalcemia is a controversial issue. The present study preliminarily investigated the effects of calcium supplementation on the length of hospitalization and mortality in septic ICU patients with different severities of hypocalcemia and disease. METHOD A total of 5761 eligible septic patients, including 2689 who received calcium supplementation and 3072 who did not receive calcium supplementation, were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The cofounding covariates between the calcium supplement and nonsupplement groups were balanced using the propensity score matching model. We compared the length of stay (LOS) in the ICU and hospital with 28-day and hospital mortality and stratified the analysis according to the sequential organ failure assessment (SOFA) score and ionized calcium (iCa) at the first ICU admission in the matched groups. RESULTS The results showed that iCa at the first ICU admission was associated with mortality in sepsis patients (HR: 0.421; 95% CI: 0.211∼0.837), but the lowest mortality rate was observed in patients with mild hypocalcemia. A total of 993 paired patients were included in the analysis after propensity score matching. Regardless of the SOFA score or presence of iCa, the LOS in the ICU was higher in the calcium supplement group than in the nonsupplement group. The survival analysis was stratified by the SOFA score and showed that calcium supplementation reduced mortality when the patient's SOFA score was ≥8 (p=0.002), and it worsened the outcome when the patient's SOFA score was ≤4 (p=0.010). It had no significant effect on patients with SOFA scores ranging from 5 to 7 (p=0.911). CONCLUSION Our results showed that mild hypocalcemia may be protective in septic patients, and calcium supplementation may have positive and negative effects on mortality depending on disease severity. The SOFA score may be a valuable clinical index for decisions regarding calcium administration.
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Affiliation(s)
- Wencheng He
- Department of Intensive Care Unit, Peking University Shenzhen Hospital, Shenzhen Peking University, The Hong Kong University of Science and Technology Medical Center, No. 1120, Lianhua Road, Futian District, Shenzhen 518000, China
- Department of Intensive Care Unit, Peking University Shenzhen Hospital, No. 1120, Lianhua Road, Futian District, Shenzhen 518000, China
| | - Lei Huang
- Department of Intensive Care Unit, Peking University Shenzhen Hospital, No. 1120, Lianhua Road, Futian District, Shenzhen 518000, China
| | - Hua Luo
- Department of Intensive Care Unit, Peking University Shenzhen Hospital, No. 1120, Lianhua Road, Futian District, Shenzhen 518000, China
| | - Jingying Chen
- Department of Intensive Care Unit, Peking University Shenzhen Hospital, No. 1120, Lianhua Road, Futian District, Shenzhen 518000, China
| | - Weijia Li
- Department of Intensive Care Unit, Peking University Shenzhen Hospital, No. 1120, Lianhua Road, Futian District, Shenzhen 518000, China
| | - Yiming Zhang
- Department of Intensive Care Unit, Peking University Shenzhen Hospital, No. 1120, Lianhua Road, Futian District, Shenzhen 518000, China
| | - Youzhong An
- Department of Intensive Care Unit, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, China
| | - Weixing Zhang
- Department of Intensive Care Unit, Peking University Shenzhen Hospital, No. 1120, Lianhua Road, Futian District, Shenzhen 518000, China
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25
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Huang L, Xiao H, Xie X, Hu F, Tang F, Smith SB, Gan L. Generation of Sigmar1 conditional knockout mouse using CRISPR-Cas9 gene targeting. Genesis 2022; 60:e23487. [PMID: 35633570 DOI: 10.1002/dvg.23487] [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: 12/17/2021] [Revised: 04/01/2022] [Accepted: 04/25/2022] [Indexed: 11/08/2022]
Abstract
The Sigma 1 receptor (SIGMAR1) is a transmembrane protein located in the mitochondria-associated endoplasmic reticulum membrane, and plays an important role in cell survival as a pluripotent modulator of a variety of signaling pathways related to neurodegeneration. Though SIGMAR1 is a potential target for neurodegenerative diseases, the specific role of SIGMAR1 in different tissue and cell types remains unclear. Here we reported the generation of Sigmar1 conditional knockout (Sigmar1loxP ) mice using CRISPR-Cas9 method to insert loxP sites into the 5'- and 3'-untranslated regions of Sigmar1. We showed that the insertion of loxP sequences did not affect the expression of Sigmar1 and that Sigmar1loxP/loxP mice exhibited no detectable visual defects compared with wild-type mice at the early adult stage. By crossing Sigmar1loxP mice with retina-specific Six3-Cre and ubiquitous CMV-Cre mice, we confirmed the deletion of Sigmar1 coding regions of exons 1-4, and the retina-specific and global loss of SIGMAR1 expression, respectively. Thus, Sigmar1loxP mice provide a valuable tool for unraveling the tissue and cell-type-specific role of Sigmar1.
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Affiliation(s)
- Liang Huang
- Department of Neuroscience and Regenerative Medicine, Augusta University Medical College of Georgia, Augusta, Georgia, USA.,Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, USA
| | - Haiyan Xiao
- Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, USA.,Department of Cellular Biology and Anatomy, Augusta University Medical College of Georgia, Augusta, Georgia, USA
| | - Xiaoling Xie
- Department of Neuroscience and Regenerative Medicine, Augusta University Medical College of Georgia, Augusta, Georgia, USA
| | - Fang Hu
- Department of Neuroscience and Regenerative Medicine, Augusta University Medical College of Georgia, Augusta, Georgia, USA
| | - Fulei Tang
- Department of Neuroscience and Regenerative Medicine, Augusta University Medical College of Georgia, Augusta, Georgia, USA
| | - Sylvia B Smith
- Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, USA.,Department of Cellular Biology and Anatomy, Augusta University Medical College of Georgia, Augusta, Georgia, USA
| | - Lin Gan
- Department of Neuroscience and Regenerative Medicine, Augusta University Medical College of Georgia, Augusta, Georgia, USA.,Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, USA
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26
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Grespi F, Vianello C, Cagnin S, Giacomello M, De Mario A. The Interplay of Microtubules with Mitochondria–ER Contact Sites (MERCs) in Glioblastoma. Biomolecules 2022; 12:biom12040567. [PMID: 35454156 PMCID: PMC9030160 DOI: 10.3390/biom12040567] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/01/2022] [Accepted: 04/06/2022] [Indexed: 11/16/2022] Open
Abstract
Gliomas are heterogeneous neoplasms, classified into grade I to IV according to their malignancy and the presence of specific histological/molecular hallmarks. The higher grade of glioma is known as glioblastoma (GB). Although progress has been made in surgical and radiation treatments, its clinical outcome is still unfavorable. The invasive properties of GB cells and glioma aggressiveness are linked to the reshaping of the cytoskeleton. Recent works suggest that the different susceptibility of GB cells to antitumor immune response is also associated with the extent and function of mitochondria–ER contact sites (MERCs). The presence of MERCs alterations could also explain the mitochondrial defects observed in GB models, including abnormalities of energy metabolism and disruption of apoptotic and calcium signaling. Based on this evidence, the question arises as to whether a MERCs–cytoskeleton crosstalk exists, and whether GB progression is linked to an altered cytoskeleton–MERCs interaction. To address this possibility, in this review we performed a meta-analysis to compare grade I and grade IV GB patients. From this preliminary analysis, we found that GB samples (grade IV) are characterized by altered expression of cytoskeletal and MERCs related genes. Among them, the cytoskeleton-associated protein 4 (CKAP4 or CLIMP-63) appears particularly interesting as it encodes a MERCs protein controlling the ER anchoring to microtubules (MTs). Although further in-depth analyses remain necessary, this perspective review may provide new hints to better understand GB molecular etiopathogenesis, by suggesting that cytoskeletal and MERCs alterations cooperate to exacerbate the cellular phenotype of high-grade GB and that MERCs players can be exploited as novel biomarkers/targets to enhance the current therapy for GB.
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Affiliation(s)
- Francesca Grespi
- Department of Biology, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy; (F.G.); (C.V.); (S.C.)
| | - Caterina Vianello
- Department of Biology, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy; (F.G.); (C.V.); (S.C.)
| | - Stefano Cagnin
- Department of Biology, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy; (F.G.); (C.V.); (S.C.)
- CRIBI Biotechnology Center, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy
- CIR-Myo Myology Center, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy
| | - Marta Giacomello
- Department of Biology, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy; (F.G.); (C.V.); (S.C.)
- Department of Biomedical Sciences, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy
- Correspondence: (M.G.); (A.D.M.)
| | - Agnese De Mario
- Department of Biomedical Sciences, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy
- Correspondence: (M.G.); (A.D.M.)
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27
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Mitochondria-Endoplasmic Reticulum Contacts: The Promising Regulators in Diabetic Cardiomyopathy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2531458. [PMID: 35450404 PMCID: PMC9017569 DOI: 10.1155/2022/2531458] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 08/04/2021] [Accepted: 03/28/2022] [Indexed: 02/05/2023]
Abstract
Diabetic cardiomyopathy (DCM), as a serious complication of diabetes, causes structural and functional abnormalities of the heart and eventually progresses to heart failure. Currently, there is no specific treatment for DCM. Studies have proved that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are key factors for the development and progression of DCM. The mitochondria-associated ER membranes (MAMs) are a unique domain formed by physical contacts between mitochondria and ER and mediate organelle communication. Under high glucose conditions, changes in the distance and composition of MAMs lead to abnormal intracellular signal transduction, which will affect the physiological function of MAMs, such as alter the Ca2+ homeostasis in cardiomyocytes, and lead to mitochondrial dysfunction and abnormal apoptosis. Therefore, the dysfunction of MAMs is closely related to the pathogenesis of DCM. In this review, we summarized the evidence for the role of MAMs in DCM and described that MAMs participated directly or indirectly in the regulation of the pathophysiological process of DCM via the regulation of Ca2+ signaling, mitochondrial dynamics, ER stress, autophagy, and inflammation. Finally, we discussed the clinical transformation prospects and technical limitations of MAMs-associated proteins (such as MFN2, FUNDC1, and GSK3β) as potential therapeutic targets for DCM.
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28
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Saini N, Lakshminarayanan S, Kundu P, Sarin A. Notch1 Modulation of Cellular Calcium Regulates Mitochondrial Metabolism and Anti-Apoptotic Activity in T-Regulatory Cells. Front Immunol 2022; 13:832159. [PMID: 35222416 PMCID: PMC8866856 DOI: 10.3389/fimmu.2022.832159] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 01/21/2022] [Indexed: 01/04/2023] Open
Abstract
As the major hub of metabolic activity and an organelle sequestering pro-apoptogenic intermediates, mitochondria lie at the crossroads of cellular decisions of death and survival. Intracellular calcium is a key regulator of these outcomes with rapid, uncontrolled uptake into mitochondria, activating pro-apoptotic cascades that trigger cell death. Here, we show that calcium uptake and mitochondrial metabolism in murine T-regulatory cells (Tregs) is tuned by Notch1 activity. Based on analysis of Tregs and the HEK cell line, we present evidence that modulation of cellular calcium dynamics underpins Notch1 regulation of mitochondrial homeostasis and consequently anti-apoptotic activity. Targeted siRNA-mediated ablations reveal dependency on molecules controlling calcium release from the endoplasmic reticulum (ER) and the chaperone, glucose-regulated protein 75 (Grp75), the associated protein Voltage Dependent Anion Channel (VDAC)1 and the Mitochondrial Calcium Uniporter (MCU), which together facilitate ER calcium transfer and uptake into the mitochondria. Endogenous Notch1 is detected in immune-complexes with Grp75 and VDAC1. Deficits in mitochondrial oxidative and survival in Notch1 deficient Tregs, were corrected by the expression of recombinant Notch1 intracellular domain, and in part by recombinant Grp75. Thus, the modulation of calcium dynamics and consequently mitochondrial metabolism underlies Treg survival in conditions of nutrient stress. This work positions a key role for Notch1 activity in these outcomes.
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Affiliation(s)
- Neetu Saini
- Regulation of Cell Fate, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bengaluru, India.,Department of Biology, Manipal Academy of Higher Education, Manipal, India
| | - Sowmya Lakshminarayanan
- National Centre for Biological Science, TATA Institute of Fundamental Research (TIFR), Bengaluru, India
| | - Priyanka Kundu
- National Centre for Biological Science, TATA Institute of Fundamental Research (TIFR), Bengaluru, India
| | - Apurva Sarin
- Regulation of Cell Fate, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bengaluru, India
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29
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Fehsel K, Christl J. Comorbidity of osteoporosis and Alzheimer's disease: Is `AKT `-ing on cellular glucose uptake the missing link? Ageing Res Rev 2022; 76:101592. [PMID: 35192961 DOI: 10.1016/j.arr.2022.101592] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 02/14/2022] [Accepted: 02/16/2022] [Indexed: 02/08/2023]
Abstract
Osteoporosis and Alzheimer's disease (AD) are both degenerative diseases. Osteoporosis often proceeds cognitive deficits, and multiple studies have revealed common triggers that lead to energy deficits in brain and bone. Risk factors for osteoporosis and AD, such as obesity, type 2 diabetes, aging, chemotherapy, vitamin deficiency, alcohol abuse, and apolipoprotein Eε4 and/or Il-6 gene variants, reduce cellular glucose uptake, and protective factors, such as estrogen, insulin, exercise, mammalian target of rapamycin inhibitors, hydrogen sulfide, and most phytochemicals, increase uptake. Glucose uptake is a fine-tuned process that depends on an abundance of glucose transporters (Gluts) on the cell surface. Gluts are stored in vesicles under the plasma membrane, and protective factors cause these vesicles to fuse with the membrane, resulting in presentation of Gluts on the cell surface. This translocation depends mainly on AKT kinase signaling and can be affected by a range of factors. Reduced AKT kinase signaling results in intracellular glucose deprivation, which causes endoplasmic reticulum stress and iron depletion, leading to activation of HIF-1α, the transcription factor necessary for higher Glut expression. The link between diseases and aging is a topic of growing interest. Here, we show that diseases that affect the same biochemical pathways tend to co-occur, which may explain why osteoporosis and/or diabetes are often associated with AD.
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30
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Afrin S, Ali M, El Sabeh M, Yang Q, Al‐Hendy A, Borahay MA. Simvastatin inhibits stem cell proliferation in human leiomyoma via TGF-β3 and Wnt/β-Catenin pathways. J Cell Mol Med 2022; 26:1684-1698. [PMID: 35118811 PMCID: PMC8899165 DOI: 10.1111/jcmm.17211] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 01/13/2022] [Accepted: 01/19/2022] [Indexed: 01/06/2023] Open
Abstract
Uterine leiomyoma (UL) is the most common gynaecologic tumour, affecting an estimated 70 to 80% of women. Leiomyomas develop from the transformation of myometrial stem cells into leiomyoma stem (or tumour-initiating) cells. These cells undergo self-renewal and differentiation to mature cells, both are necessary for the maintenance of tumour stem cell niche and tumour growth, respectively. Wnt/β-catenin and TGF-β/SMAD pathways, both overactive in UL, promote stem cell self-renewal, crosstalk between stem and mature cells, cellular proliferation, extracellular matrix (ECM) accumulation and drive overall UL growth. Recent evidence suggests that simvastatin, an antihyperlipidemic drug, may have anti-leiomyoma properties. Herein, we investigated the effects of simvastatin on UL stem cells. We isolated leiomyoma stem cells by flow cytometry using DyeCycle Violet staining and Stro-1/CD44 surface markers. We found that simvastatin inhibits proliferation and induces apoptosis in UL stem cells. In addition, it also suppressed the expression of the stemness markers Nanog, Oct4 and Sox2. Simvastatin significantly decreased the production of the key ECM proteins, collagen 1 and fibronectin. Finally, it inhibited genes and/or proteins expression of TGF-β1, 2 and 3, SMAD2, SMAD4, Wnt4, β-Catenin, LRP6, AXIN2 and Cyclin D1 in UL stem cells, all are key drivers of the TGF-β3/SMAD2 and Wnt4/β-Catenin pathways. Thus, we have identified a novel stem cell-targeting anti-leiomyoma simvastatin effect. Further studies are needed to replicate these findings in vivo.
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Affiliation(s)
- Sadia Afrin
- Department of Gynecology and ObstetricsJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Mohamed Ali
- Clinical Pharmacy DepartmentFaculty of PharmacyAin Shams UniversityCairoEgypt
| | - Malak El Sabeh
- Department of Gynecology and ObstetricsJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Qiwei Yang
- Department of Gynecology and ObstetricsUniversity of Chicago School of MedicineChicagoIllinoisUSA
| | - Ayman Al‐Hendy
- Department of Gynecology and ObstetricsUniversity of Chicago School of MedicineChicagoIllinoisUSA
| | - Mostafa A. Borahay
- Department of Gynecology and ObstetricsJohns Hopkins University School of MedicineBaltimoreMarylandUSA
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31
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Targeting autophagy, oxidative stress, and ER stress for neurodegenerative diseases treatment. J Control Release 2022; 345:147-175. [DOI: 10.1016/j.jconrel.2022.03.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/27/2022] [Accepted: 03/01/2022] [Indexed: 12/13/2022]
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32
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Wang D, He X, Zheng C, Wang C, Peng P, Gao C, Xu X, Ma Y, Liu M, Yang L, Luo Z. Endoplasmic Reticulum Stress: An Emerging Therapeutic Target for Intervertebral Disc Degeneration. Front Cell Dev Biol 2022; 9:819139. [PMID: 35178406 PMCID: PMC8843852 DOI: 10.3389/fcell.2021.819139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 12/24/2021] [Indexed: 12/22/2022] Open
Abstract
Low back pain (LBP) is a global health issue. Intervertebral disc degeneration (IDD) is a major cause of LBP. Although the explicit mechanisms underpinning IDD are unclear, endoplasmic reticulum (ER) stress caused by aberrant unfolded or misfolded proteins may be involved. The accumulation of unfolded/misfolded proteins may result in reduced protein synthesis and promote aberrant protein degradation to recover ER function, a response termed the unfolded protein response. A growing body of literature has demonstrated the potential relationships between ER stress and the pathogenesis of IDD, indicating some promising therapeutic targets. In this review, we summarize the current knowledge regarding the impact of ER stress on the process of IDD, as well as some potential therapeutic strategies for alleviating disc degeneration by targeting different pathways to inhibit ER stress. This review will facilitate understanding the pathogenesis and progress of IDD and highlights potential therapeutic targets for treating this condition.
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Affiliation(s)
- Dong Wang
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xin He
- Pharmacy Department, Air Force Hospital of Eastern Theater Command, Nanjing, China
| | - Chao Zheng
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Chengzhe Wang
- Rehabilitation Department, Dongchangfu Traditional Chinese Medicine Hospital, Liaocheng, China
| | - Pandi Peng
- Institute of Flexible Electronics, Northwestern Polytechnical University, Xi'an, China
| | - Chu Gao
- Medical Research Institute, Northwestern Polytechnical University, Xi'an, China
| | - Xiaolong Xu
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yachao Ma
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Mei Liu
- Pharmacy Department, Air Force Hospital of Eastern Theater Command, Nanjing, China
| | - Liu Yang
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.,Medical Research Institute, Northwestern Polytechnical University, Xi'an, China
| | - Zhuojing Luo
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.,Medical Research Institute, Northwestern Polytechnical University, Xi'an, China
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TREX1 Deficiency Induces ER Stress-Mediated Neuronal Cell Death by Disrupting Ca 2+ Homeostasis. Mol Neurobiol 2022; 59:1398-1418. [PMID: 34997539 PMCID: PMC8882114 DOI: 10.1007/s12035-021-02631-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 11/01/2021] [Indexed: 11/09/2022]
Abstract
TREX1 is an exonuclease that degrades extranuclear DNA species in mammalian cells. Herein, we show a novel mechanism by which TREX1 interacts with the BiP/GRP78 and TREX1 deficiency triggers ER stress through the accumulation of single-stranded DNA and activates unfolded protein response (UPR) signaling via the disruption of the TREX1-BiP/GRP78 interaction. In TREX1 knockdown cells, the activation of ER stress signaling disrupted ER Ca2+ homeostasis via the ERO1α-IP3R1-CaMKII pathway, leading to neuronal cell death. Moreover, TREX1 knockdown dysregulated the Golgi-microtubule network through Golgi fragmentation and decreased Ac-α-tubulin levels, contributing to neuronal injury. These alterations were also observed in neuronal cells harboring a TREX1 mutation (V91M) that has been identified in hereditary spastic paraplegia (HSP) patients in Korea. Notably, this mutation leads to defects in the TREX1-BiP/GRP78 interaction and mislocalization of TREX1 from the ER and possible disruption of the Golgi-microtubule network. In summary, the current study reveals TREX1 as a novel regulator of the BiP/GRP78 interaction and shows that TREX1 deficiency promotes ER stress-mediated neuronal cell death, which indicates that TREX1 may hold promise as a therapeutic target for neurodegenerative diseases such as HSP.
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Khaksar S, Bigdeli M, Samiee A, Shirazi-zand Z. Antioxidant and Anti-apoptotic Effects of Cannabidiol in Model of Ischemic Stroke in Rats. Brain Res Bull 2022; 180:118-130. [DOI: 10.1016/j.brainresbull.2022.01.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/27/2021] [Accepted: 01/05/2022] [Indexed: 12/11/2022]
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Ning B, Guo C, Kong A, Li K, Xie Y, Shi H, Gu J. Calcium Signaling Mediates Cell Death and Crosstalk with Autophagy in Kidney Disease. Cells 2021; 10:cells10113204. [PMID: 34831428 PMCID: PMC8622220 DOI: 10.3390/cells10113204] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/09/2021] [Accepted: 11/13/2021] [Indexed: 12/15/2022] Open
Abstract
The kidney is an important organ for the maintenance of Ca2+ homeostasis in the body. However, disruption of Ca2+ homeostasis will cause a series of kidney diseases, such as acute kidney injury (AKI), chronic kidney disease (CKD), renal ischemia/reperfusion (I/R) injury, autosomal dominant polycystic kidney disease (ADPKD), podocytopathy, and diabetic nephropathy. During the progression of kidney disease, Ca2+ signaling plays key roles in various cell activities such as necrosis, apoptosis, eryptosis and autophagy. Importantly, there are complex Ca2+ flux networks between the endoplasmic reticulum (ER), mitochondria and lysosomes which regulate intracellular Ca2+ signaling in renal cells and contribute to kidney disease. In addition, Ca2+ signaling also links the crosstalk between various cell deaths and autophagy under the stress of heavy metals or high glucose. In this regard, we present a review of Ca2+ signaling in cell death and crosstalk with autophagy and its potential as a therapeutic target for the development of new and efficient drugs against kidney diseases.
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Affiliation(s)
- Bo Ning
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
| | - Chuanzhi Guo
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
| | - Anqi Kong
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
| | - Kongdong Li
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
| | - Yimin Xie
- Affiliated Hospital of Jiangsu University—Yixing Hospital, Yixing 214200, China;
| | - Haifeng Shi
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
| | - Jie Gu
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
- Correspondence: ; Tel.: +86-0511-88791923
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Live-cell visualization of cytochrome c: a tool to explore apoptosis. Biochem Soc Trans 2021; 49:2903-2915. [PMID: 34747968 DOI: 10.1042/bst20211028] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/10/2021] [Accepted: 10/12/2021] [Indexed: 02/07/2023]
Abstract
Apoptosis dysfunction is associated with several malignancies, including cancer and autoimmune diseases. Apoptosis restoration could be an attractive therapeutic approach to those diseases. Mitochondrial outer membrane permeabilization is regarded as the point of no return in the 'classical' apoptosis triggering pathway. Cytoplasmic release of cytochrome c (cyt c), a mitochondrial electron transporter, is a prominent indicator of such critical step. Therefore, visualizing cyt c efflux in living cells is a convenient approach to address apoptosis triggering and monitor performance of apoptosis restoration strategies. Recent years have been prolific in the development of biosensors to visualize cyt c mitochondrial efflux in living cells, by fluorescence microscopy. These biosensors specifically detect endogenous, untagged cyt c, while showing efficient cellular uptake and reduced cell toxicity. A common aspect is their fluorescence quenching in the absence or presence of bound cyt c, resulting in two main biosensor types: 'turn ON' and 'turn OFF'. In some of these systems, fluorescence intensity of fluorophore-bound aptamers is enhanced upon cyt c binding. In others, cyt c binding to quantum dots quenches their fluorescence. In the present minireview, I describe these biosensors and briefly introduce some hypotheses that could be addressed using these novel tools.
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Yamashita R, Fujii S, Ushioda R, Nagata K. Ca 2+ imbalance caused by ERdj5 deletion affects mitochondrial fragmentation. Sci Rep 2021; 11:20772. [PMID: 34728782 PMCID: PMC8563984 DOI: 10.1038/s41598-021-99980-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 09/28/2021] [Indexed: 11/29/2022] Open
Abstract
The endoplasmic reticulum (ER) is the organelle responsible for the folding of secretory/membrane proteins and acts as a dynamic calcium ion (Ca2+) store involved in various cellular signalling pathways. Previously, we reported that the ER-resident disulfide reductase ERdj5 is involved in the ER-associated degradation (ERAD) of misfolded proteins in the ER and the activation of SERCA2b, a Ca2+ pump on the ER membrane. These results highlighted the importance of the regulation of redox activity in both Ca2+ and protein homeostasis in the ER. Here, we show that the deletion of ERdj5 causes an imbalance in intracellular Ca2+ homeostasis, the activation of Drp1, a cytosolic GTPase involved in mitochondrial fission, and finally the aberrant fragmentation of mitochondria, which affects cell viability as well as phenotype with features of cellular senescence. Thus, ERdj5-mediated regulation of intracellular Ca2+ is essential for the maintenance of mitochondrial homeostasis involved in cellular senescence.
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Affiliation(s)
- Riyuji Yamashita
- Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, 603-8555, Japan
| | - Shohei Fujii
- Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, 603-8555, Japan
| | - Ryo Ushioda
- Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, 603-8555, Japan. .,Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto, 605-8555, Japan.
| | - Kazuhiro Nagata
- Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, 603-8555, Japan. .,Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto, 605-8555, Japan. .,JT Biohistory Research Hall, Murasaki Town 1-1, Takatsuki City, Osaka, 569-1125, Japan.
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The Multifaceted Therapeutic Mechanisms of Curcumin in Osteosarcoma: State-of-the-Art. JOURNAL OF ONCOLOGY 2021; 2021:3006853. [PMID: 34671398 PMCID: PMC8523229 DOI: 10.1155/2021/3006853] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/24/2021] [Indexed: 12/16/2022]
Abstract
Osteosarcoma is a major form of malignant bone tumor that typically occurs in young adults and children. The combination of aggressive surgical strategies and chemotherapy has led to improvements in survival time, although individuals with recurrent or metastatic conditions still have an extremely poor prognosis. This disappointing situation strongly indicates that testing novel, targeted therapeutic agents is imperative to prevent the progression of osteosarcoma and enhance patient survival time. Curcumin, a naturally occurring phenolic compound found in Curcuma longa, has been shown to have a wide variety of anti-tumor, anti-oxidant, and anti-inflammatory activities in many types of cancers including osteosarcoma. Curcumin is a highly pleiotropic molecule that can modulate intracellular signaling pathways to regulate cell proliferation, inflammation, and apoptosis. These signaling pathways include RANK/RANKL, Notch, Wnt/β-catenin, apoptosis, autophagy, JAK/STAT, and HIF-1 pathways. Additionally, curcumin can regulate the expression of various types of microRNAs that are involved in osteosarcoma. Therefore, curcumin may be a potential candidate for the prevention and treatment of osteosarcoma. This comprehensive review not only covers the use of curcumin in the treatment of osteosarcoma and its anti-cancer molecular mechanisms but also reveals the novel delivery strategies and combination therapies with the aim to improve the therapeutic effect of curcumin.
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Wang HX, Zhang R, Li Z, Wang LS, Yu Y, Wang Q, Ding Z, Zhang JP, Zhang MR, Xu LC. Cypermethrin induces Sertoli cell apoptosis through mitochondrial pathway associated with calcium. Toxicol Res (Camb) 2021; 10:742-750. [PMID: 34484665 DOI: 10.1093/toxres/tfab056] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 04/09/2021] [Accepted: 05/31/2021] [Indexed: 12/13/2022] Open
Abstract
Cypermethrin, one kind of pyrethroid pesticides, has been shown to act as endocrine-disrupting chemicals (EDCs). The purpose of this study was to explore the roles of Sertoli cell apoptosis through mitochondrial pathway associated with calcium (Ca2+) in cypermethrin-induced male reproductive toxicology. The mouse Sertoli cells TM4 were cultured with 0 μM, 10 μM, 20 μM, 40 μM and 80 μM of cypermethrin. We used flow cytometry, Fluo-4 AM, western blot and JC-1 Assay Kit to examine apoptosis, intracellular Ca2+, expressions of mitochondrial apoptotic pathway-related proteins and mitochondrial membrane potential. We found cypermethrin increased apoptosis rate of TM4 cells significantly and with a significant increase in intracellular Ca2+ concentration. Cypermethrin significantly decreased the protein expressions of cytosolic B-cell lymphoma-2 (Bcl-2) and mitochondrial cytochrome c (Cyt-c). The protein expressions of cytosolic Bcl-2-associated x (Bax), Cyt-c, cleaved caspase-3, calmodulin (CaM), Ca2+/CaM-dependent protein kinases II (CaMKII) and phosphorylated CaMKII were increased significantly in cypermethrin-exposed TM4 cells. Cypermethrin decreased mitochondrial membrane potential significantly. Then, Bcl-2 family and Ca2+/CaM/CaMKII pathway participate in cypermethrin-induced homeostasis. Ca2+ overload activates mitochondrial pathway by increasing permeability of mitochondrial membrane and decreasing mitochondrial membrane potential. We suggest cypermethrin induces Sertoli cell apoptosis involving mitochondrial pathway associated with Ca2+ regulated by Bcl-2 family and Ca2+/CaM/CaMKII pathway. The study provides a new insight into mechanisms involved in cypermethrin-induced male reproductive toxicology.
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Affiliation(s)
- Heng-Xue Wang
- Key Lab of Environment and Health, School of Public Health, Xuzhou Medical University, Xuzhou 221004, 209 Tong-Shan Road, Xuzhou, Jiangsu, China
| | - Rui Zhang
- Key Lab of Environment and Health, School of Public Health, Xuzhou Medical University, Xuzhou 221004, 209 Tong-Shan Road, Xuzhou, Jiangsu, China
| | - Zheng Li
- Key Lab of Environment and Health, School of Public Health, Xuzhou Medical University, Xuzhou 221004, 209 Tong-Shan Road, Xuzhou, Jiangsu, China
| | - Lu-Shan Wang
- Key Lab of Environment and Health, School of Public Health, Xuzhou Medical University, Xuzhou 221004, 209 Tong-Shan Road, Xuzhou, Jiangsu, China
| | - Yue Yu
- Key Lab of Environment and Health, School of Public Health, Xuzhou Medical University, Xuzhou 221004, 209 Tong-Shan Road, Xuzhou, Jiangsu, China
| | - Qi Wang
- Key Lab of Environment and Health, School of Public Health, Xuzhou Medical University, Xuzhou 221004, 209 Tong-Shan Road, Xuzhou, Jiangsu, China
| | - Zhen Ding
- Key Lab of Environment and Health, School of Public Health, Xuzhou Medical University, Xuzhou 221004, 209 Tong-Shan Road, Xuzhou, Jiangsu, China
| | - Jin-Peng Zhang
- Key Lab of Environment and Health, School of Public Health, Xuzhou Medical University, Xuzhou 221004, 209 Tong-Shan Road, Xuzhou, Jiangsu, China
| | - Mei-Rong Zhang
- Key Lab of Environment and Health, School of Public Health, Xuzhou Medical University, Xuzhou 221004, 209 Tong-Shan Road, Xuzhou, Jiangsu, China
| | - Li-Chun Xu
- Key Lab of Environment and Health, School of Public Health, Xuzhou Medical University, Xuzhou 221004, 209 Tong-Shan Road, Xuzhou, Jiangsu, China
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40
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González‐Arzola K, Guerra‐Castellano A, Rivero‐Rodríguez F, Casado‐Combreras MÁ, Pérez‐Mejías G, Díaz‐Quintana A, Díaz‐Moreno I, De la Rosa MA. Mitochondrial cytochrome c shot towards histone chaperone condensates in the nucleus. FEBS Open Bio 2021; 11:2418-2440. [PMID: 33938164 PMCID: PMC8409293 DOI: 10.1002/2211-5463.13176] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 04/26/2021] [Indexed: 12/15/2022] Open
Abstract
Despite mitochondria being key for the control of cell homeostasis and fate, their role in DNA damage response is usually just regarded as an apoptotic trigger. However, growing evidence points to mitochondrial factors modulating nuclear functions. Remarkably, after DNA damage, cytochrome c (Cc) interacts in the cell nucleus with a variety of well-known histone chaperones, whose activity is competitively inhibited by the haem protein. As nuclear Cc inhibits the nucleosome assembly/disassembly activity of histone chaperones, it might indeed affect chromatin dynamics and histone deposition on DNA. Several histone chaperones actually interact with Cc Lys residues through their acidic regions, which are also involved in heterotypic interactions leading to liquid-liquid phase transitions responsible for the assembly of nuclear condensates, including heterochromatin. This relies on dynamic histone-DNA interactions that can be modulated by acetylation of specific histone Lys residues. Thus, Cc may have a major regulatory role in DNA repair by fine-tuning nucleosome assembly activity and likely nuclear condensate formation.
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Affiliation(s)
- Katiuska González‐Arzola
- Institute for Chemical Research (IIQ)Scientific Research Centre Isla de la Cartuja (cicCartuja)University of Seville – CSICSpain
| | - Alejandra Guerra‐Castellano
- Institute for Chemical Research (IIQ)Scientific Research Centre Isla de la Cartuja (cicCartuja)University of Seville – CSICSpain
| | - Francisco Rivero‐Rodríguez
- Institute for Chemical Research (IIQ)Scientific Research Centre Isla de la Cartuja (cicCartuja)University of Seville – CSICSpain
| | - Miguel Á. Casado‐Combreras
- Institute for Chemical Research (IIQ)Scientific Research Centre Isla de la Cartuja (cicCartuja)University of Seville – CSICSpain
| | - Gonzalo Pérez‐Mejías
- Institute for Chemical Research (IIQ)Scientific Research Centre Isla de la Cartuja (cicCartuja)University of Seville – CSICSpain
| | - Antonio Díaz‐Quintana
- Institute for Chemical Research (IIQ)Scientific Research Centre Isla de la Cartuja (cicCartuja)University of Seville – CSICSpain
| | - Irene Díaz‐Moreno
- Institute for Chemical Research (IIQ)Scientific Research Centre Isla de la Cartuja (cicCartuja)University of Seville – CSICSpain
| | - Miguel A. De la Rosa
- Institute for Chemical Research (IIQ)Scientific Research Centre Isla de la Cartuja (cicCartuja)University of Seville – CSICSpain
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41
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Olivas-Aguirre M, Torres-López L, Gómez-Sandoval Z, Villatoro-Gómez K, Pottosin I, Dobrovinskaya O. Tamoxifen Sensitizes Acute Lymphoblastic Leukemia Cells to Cannabidiol by Targeting Cyclophilin-D and Altering Mitochondrial Ca 2+ Homeostasis. Int J Mol Sci 2021; 22:8688. [PMID: 34445394 PMCID: PMC8395529 DOI: 10.3390/ijms22168688] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/16/2021] [Accepted: 07/17/2021] [Indexed: 11/16/2022] Open
Abstract
Cytotoxic effects of cannabidiol (CBD) and tamoxifen (TAM) have been observed in several cancer types. We have recently shown that CBD primarily targets mitochondria, inducing a stable mitochondrial permeability transition pore (mPTP) and, consequently, the death of acute lymphoblastic leukemia (T-ALL) cells. Mitochondria have also been documented among cellular targets for the TAM action. In the present study we have demonstrated a synergistic cytotoxic effect of TAM and CBD against T-ALL cells. By measuring the mitochondrial membrane potential (ΔΨm), mitochondrial calcium ([Ca2+]m) and protein-ligand docking analysis we determined that TAM targets cyclophilin D (CypD) to inhibit mPTP formation. This results in a sustained [Ca2+]m overload upon the consequent CBD administration. Thus, TAM acting on CypD sensitizes T-ALL to mitocans such as CBD by altering the mitochondrial Ca2+ homeostasis.
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Affiliation(s)
- Miguel Olivas-Aguirre
- Laboratory of Immunobiology and Ionic Transport Regulation, Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Av. 25 de Julio 965, Villa de San Sebastián, Colima 28045, Mexico; (M.O.-A.); (L.T.-L.); (K.V.-G.)
| | - Liliana Torres-López
- Laboratory of Immunobiology and Ionic Transport Regulation, Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Av. 25 de Julio 965, Villa de San Sebastián, Colima 28045, Mexico; (M.O.-A.); (L.T.-L.); (K.V.-G.)
| | - Zeferino Gómez-Sandoval
- Facultad de Ciencias Químicas, Universidad de Colima, Carretera Colima-Coquimatlán, km. 9, Coquimatlán 28400, Mexico;
| | - Kathya Villatoro-Gómez
- Laboratory of Immunobiology and Ionic Transport Regulation, Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Av. 25 de Julio 965, Villa de San Sebastián, Colima 28045, Mexico; (M.O.-A.); (L.T.-L.); (K.V.-G.)
| | - Igor Pottosin
- Laboratory of Immunobiology and Ionic Transport Regulation, Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Av. 25 de Julio 965, Villa de San Sebastián, Colima 28045, Mexico; (M.O.-A.); (L.T.-L.); (K.V.-G.)
| | - Oxana Dobrovinskaya
- Laboratory of Immunobiology and Ionic Transport Regulation, Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Av. 25 de Julio 965, Villa de San Sebastián, Colima 28045, Mexico; (M.O.-A.); (L.T.-L.); (K.V.-G.)
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Murali Mahadevan H, Hashemiaghdam A, Ashrafi G, Harbauer AB. Mitochondria in Neuronal Health: From Energy Metabolism to Parkinson's Disease. Adv Biol (Weinh) 2021; 5:e2100663. [PMID: 34382382 DOI: 10.1002/adbi.202100663] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 06/30/2021] [Indexed: 01/01/2023]
Abstract
Mitochondria are the main suppliers of neuronal adenosine triphosphate and play a critical role in brain energy metabolism. Mitochondria also serve as Ca2+ sinks and anabolic factories and are therefore essential for neuronal function and survival. Dysregulation of neuronal bioenergetics is increasingly implicated in neurodegenerative disorders, particularly Parkinson's disease. This review describes the role of mitochondria in energy metabolism under resting conditions and during synaptic transmission, and presents evidence for the contribution of neuronal mitochondrial dysfunction to Parkinson's disease.
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Affiliation(s)
| | - Arsalan Hashemiaghdam
- Department of Cell Biology and Physiology, Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
| | - Ghazaleh Ashrafi
- Department of Cell Biology and Physiology, Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
| | - Angelika Bettina Harbauer
- Max-Planck-Institute for Neurobiology, 82152, Martinsried, Germany.,Technical University of Munich, Institute of Neuronal Cell Biology, 80333, Munich, Germany.,Munich Cluster for Systems Neurology, Munich, Germany
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43
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Abstract
Significance: The molecular processes that determine Huntington's disease (HD) pathogenesis are not yet fully understood, and until now no effective neuroprotective therapeutic strategies have been developed. Mitochondria are one of most important organelles required for neuronal homeostasis, by providing metabolic pathways relevant for energy production, regulating calcium homeostasis, or controlling free radical generation and cell death. Because augmented reactive oxygen species (ROS) accompanied by mitochondrial dysfunction are relevant early HD mechanisms, targeting these cellular mechanisms may constitute relevant therapeutic approaches. Recent Advances: Previous findings point toward a close relationship between mitochondrial dysfunction and redox changes in HD. Mutant huntingtin (mHTT) can directly interact with mitochondrial proteins, as translocase of the inner membrane 23 (TIM23), disrupting mitochondrial proteostasis and favoring ROS production and HD progression. Furthermore, abnormal brain and muscle redox signaling contributes to altered proteostasis and motor impairment in HD, which can be improved with the mitochondria-targeted antioxidant mitoquinone or resveratrol, an SIRT1 activator that ameliorates mitochondrial biogenesis and function. Critical Issues: Various antioxidants and metabolic enhancers have been studied in HD; however, the real outcome of these molecules is still debatable. New compounds have proven to ameliorate mitochondrial and redox-based signaling pathways in early stages of HD, potentially precluding selective neurodegeneration. Future Directions: Unraveling the molecular etiology of deregulated mitochondrial function and dynamics, and oxidative stress opens new prospects for HD therapeutics. In this review, we explore the role of redox unbalance and mitochondrial dysfunction in HD progression, and further describe advances on clinical trials in HD based on mitochondrial and redox-based therapeutic strategies.
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Affiliation(s)
- Lígia Fão
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.,Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Ana Cristina Rego
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.,Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
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44
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Liakath-Ali K, Südhof TC. The Perils of Navigating Activity-Dependent Alternative Splicing of Neurexins. Front Mol Neurosci 2021; 14:659681. [PMID: 33767611 PMCID: PMC7985251 DOI: 10.3389/fnmol.2021.659681] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 02/16/2021] [Indexed: 11/13/2022] Open
Abstract
Neurexins are presynaptic cell-adhesion molecules essential for synaptic function that are expressed in thousands of alternatively spliced isoforms. Recent studies suggested that alternative splicing at splice site 4 (SS4) of Nrxn1 is tightly regulated by an activity-dependent mechanism. Given that Nrxn1 alternative splicing at SS4 controls NMDA-receptor-mediated synaptic responses, activity-dependent SS4 alternative splicing would suggest a new synaptic plasticity mechanism. However, conflicting results confound the assessment of neurexin alternative splicing, prompting us to re-evaluate this issue. We find that in cortical cultures, membrane depolarization by elevated extracellular K+-concentrations produced an apparent shift in Nrxn1-SS4 alternative splicing by inducing neuronal but not astroglial cell death, resulting in persistent astroglial Nrxn1-SS4+ expression and decreased neuronal Nrxn1-SS4- expression. in vivo, systemic kainate-induced activation of neurons in the hippocampus produced no changes in Nrxn1-SS4 alternative splicing. Moreover, focal kainate injections into the mouse cerebellum induced small changes in Nrxn1-SS4 alternative splicing that, however, were associated with large decreases in Nrxn1 expression and widespread DNA damage. Our results suggest that although Nrxn1-SS4 alternative splicing may represent a mechanism of activity-dependent synaptic plasticity, common procedures for testing this hypothesis are prone to artifacts, and more sophisticated approaches will be necessary to test this important question.
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Affiliation(s)
- Kif Liakath-Ali
- Howard Hughes Medical Institute, Stanford University, Stanford, CA, United States
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, United States
| | - Thomas C. Südhof
- Howard Hughes Medical Institute, Stanford University, Stanford, CA, United States
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, United States
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45
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Tanwar J, Singh JB, Motiani RK. Molecular machinery regulating mitochondrial calcium levels: The nuts and bolts of mitochondrial calcium dynamics. Mitochondrion 2021; 57:9-22. [PMID: 33316420 PMCID: PMC7610953 DOI: 10.1016/j.mito.2020.12.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/18/2020] [Accepted: 12/03/2020] [Indexed: 02/06/2023]
Abstract
Mitochondria play vital role in regulating the cellular energetics and metabolism. Further, it is a signaling hub for cell survival and apoptotic pathways. One of the key determinants that calibrate both cellular energetics and survival functions is mitochondrial calcium (Ca2+) dynamics. Mitochondrial Ca2+ regulates three Ca2+-sensitive dehydrogenase enzymes involved in tricarboxylic acid cycle (TCA) cycle thereby directly controlling ATP synthesis. On the other hand, excessive Ca2+ concentration within the mitochondrial matrix elevates mitochondrial reactive oxygen species (mROS) levels and causes mitochondrial membrane depolarization. This leads to opening of the mitochondrial permeability transition pore (mPTP) and release of cytochrome c into cytosol eventually triggering apoptosis. Therefore, it is critical for cell to maintain mitochondrial Ca2+ concentration. Since cells can neither synthesize nor metabolize Ca2+, it is the dynamic interplay of Ca2+ handling proteins involved in mitochondrial Ca2+ influx and efflux that take the center stage. In this review we would discuss the key molecular machinery regulating mitochondrial Ca2+ concentration. We would focus on the channel complex involved in bringing Ca2+ into mitochondrial matrix i.e. Mitochondrial Ca2+ Uniporter (MCU) and its key regulators Mitochondrial Ca2+ Uptake proteins (MICU1, 2 and 3), MCU regulatory subunit b (MCUb), Essential MCU Regulator (EMRE) and Mitochondrial Ca2+ Uniporter Regulator 1 (MCUR1). Further, we would deliberate on major mitochondrial Ca2+ efflux proteins i.e. Mitochondrial Na+/Ca2+/Li+ exchanger (NCLX) and Leucine zipper EF hand-containing transmembrane1 (Letm1). Moreover, we would highlight the physiological functions of these proteins and discuss their relevance in human pathophysiology. Finally, we would highlight key outstanding questions in the field.
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Affiliation(s)
- Jyoti Tanwar
- CSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi 10025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Jaya Bharti Singh
- Laboratory of Calciomics and Systemic Pathophysiology (LCSP), Regional Centre for Biotechnology (RCB), Faridabad, Delhi-NCR, India
| | - Rajender K Motiani
- Laboratory of Calciomics and Systemic Pathophysiology (LCSP), Regional Centre for Biotechnology (RCB), Faridabad, Delhi-NCR, India.
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46
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Mitochondrial metabolism and calcium homeostasis in the development of NAFLD leading to hepatocellular carcinoma. Mitochondrion 2021; 58:24-37. [PMID: 33581332 DOI: 10.1016/j.mito.2021.01.007] [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] [Received: 08/29/2020] [Revised: 01/21/2021] [Accepted: 01/25/2021] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome characterized by excessive accumulation of hepatic lipid droplets. The disease progresses with steatosis as the premise for hepatocytic damage and tissue scarring, often culminating in hepatocellular carcinoma (HCC). Perturbations in mitochondrial metabolism and energetics were found to be associated with, and often instrumental in various stages of this progression. Functional impairment of the mitochondria affects all aspects of cellular functioning and a particularly important one is calcium signalling. Changes in mitochondrial calcium specifically in hepatocytes of a fatty liver, is reflected by alterations in calcium signalling as well as calcium transporter activities. This deranged Ca2+ homeostasis aids in even more uptake of lipids into the mitochondria and a shift in equilibrium, both metabolically as well as in terms of energy production, leading to completely altered cellular states. These alterations have been reviewed as a perspective to understand the disease progression through NAFLD leading to HCC.
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47
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Yu H, Sun C, Gong Q, Feng D. Mitochondria-Associated Endoplasmic Reticulum Membranes in Breast Cancer. Front Cell Dev Biol 2021; 9:629669. [PMID: 33634130 PMCID: PMC7902067 DOI: 10.3389/fcell.2021.629669] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 01/08/2021] [Indexed: 11/23/2022] Open
Abstract
Mitochondria-associated ER membranes (MAMs) represent a crucial intracellular signaling hub, that regulates various cellular events including Ca2+ homeostasis, lipid metabolism, mitochondrial function, and cellular survival and death. All of these MAM-mediated cellular events contribute to carcinogenesis. Indeed, altered functions of MAMs in several types of cancers have been documented, in particular for breast cancer. Over the past years, altered expression of many MAM-resident proteins have been reported in breast cancer. These MAM-resident proteins play an important role in regulation of breast cancer initiation and progression. In the current review, we discuss our current knowledge about the functions of MAMs, and address the underlying mechanisms through which MAM-resident proteins regulate breast cancer. A fuller understanding of the pathways through which MAMs regulate breast cancer, and identification of breast cancer-specific MAM-resident proteins may help to develop novel therapeutic strategies for breast cancer.
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Affiliation(s)
- Hongjiao Yu
- Department of Biochemistry and Molecular Biology, Guangzhou Medical University-Guangzhou Institutes of Biomedicine and Health (GMU-GIBH) Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China
| | - Chaonan Sun
- Department of Biochemistry and Molecular Biology, Guangzhou Medical University-Guangzhou Institutes of Biomedicine and Health (GMU-GIBH) Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China
| | - Qing Gong
- Department of Biochemistry and Molecular Biology, Guangzhou Medical University-Guangzhou Institutes of Biomedicine and Health (GMU-GIBH) Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China
| | - Du Feng
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
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48
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Gorabi AM, Aslani S, Barreto GE, Báez-Jurado E, Kiaie N, Jamialahmadi T, Sahebkar A. The potential of mitochondrial modulation by neuroglobin in treatment of neurological disorders. Free Radic Biol Med 2021; 162:471-477. [PMID: 33166649 DOI: 10.1016/j.freeradbiomed.2020.11.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/20/2020] [Accepted: 11/02/2020] [Indexed: 01/18/2023]
Abstract
Neuroglobin is the third member of the globin family to be identified in 2000 in neurons of both human and mouse nervous systems. Neuroglobin is an oxygen-binding globin found in neurons within the central nervous system as well as in peripheral neurons, that produces a protective effect against hypoxic/ischemic damage induced by promoting oxygen availability within the mitochondria. Numerous investigations have demonstrated that impaired neuroglobin functioning is implicated in the pathogenesis of multiple neurodegenerative disorders. Several in vitro and animal studies have reported the potential of neuroglobin upregulation in improving the neuroprotection through modulation of mitochondrial functions, such as ATP production, clearing reactive oxygen species (ROS), promoting the dynamics of mitochondria, and controlling apoptosis. Neuroglobin acts as a stress-inducible globin, which has been associated hypoxic/ischemic insults where it acts to protect the heart and brain, providing a wide range of applicability in the treatment of human disorders. This review article discusses normal physiological functions of neuroglobin in mitochondria-associated pathways, as well as outlining how dysregulation of neuroglobin is associated with the pathogenesis of neurodegenerative disorders.
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Affiliation(s)
- Armita Mahdavi Gorabi
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Aslani
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - George E Barreto
- Department of Biological Sciences, University of Limerick, Limerick, Ireland; Health Research Institute, University of Limerick, Limerick, Ireland
| | - Eliana Báez-Jurado
- Departamento de Química, Facultad de Ciencias, Universidad Antonio Nariño, Bogotá D.C., Colombia
| | - Nasim Kiaie
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Tannaz Jamialahmadi
- Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran; Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland; Halal Research Center of IRI, FDA, Tehran, Iran.
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49
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Parys JB, Bultynck G, Vervliet T. IP 3 Receptor Biology and Endoplasmic Reticulum Calcium Dynamics in Cancer. PROGRESS IN MOLECULAR AND SUBCELLULAR BIOLOGY 2021; 59:215-237. [PMID: 34050869 DOI: 10.1007/978-3-030-67696-4_11] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Intracellular Ca2+ signaling regulates a plethora of cellular functions. A central role in these processes is reserved for the inositol 1,4,5-trisphosphate receptor (IP3R), a ubiquitously expressed Ca2+-release channel, mainly located in the endoplasmic reticulum (ER). Three IP3R isoforms (IP3R1, IP3R2 and IP3R3) exist, encoded respectively by ITPR1, ITPR2 and ITPR3. The proteins encoded by these genes are each about 2700 amino acids long and assemble into large tetrameric channels, which form the target of many regulatory proteins, including several tumor suppressors and oncogenes. Due to the important role of the IP3Rs in cell function, their dysregulation is linked to multiple pathologies. In this review, we highlight the complex role of the IP3R in cancer, as it participates in most of the so-called "hallmarks of cancer". In particular, the IP3R directly controls cell death and cell survival decisions via regulation of autophagy and apoptosis. Moreover, the IP3R impacts cellular proliferation, migration and invasion. Typical examples of the role of the IP3Rs in these various processes are discussed. The relative levels of the IP3R isoforms expressed and their subcellular localization, e.g. at the ER-mitochondrial interface, is hereby important. Finally, evidence is provided about how the knowledge of the regulation of the IP3R by tumor suppressors and oncogenes can be exploited to develop novel therapeutic approaches to fight cancer.
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Affiliation(s)
- Jan B Parys
- Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
| | - Geert Bultynck
- Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Cancer Institute, KU Leuven, Leuven, Belgium
| | - Tim Vervliet
- Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Cancer Institute, KU Leuven, Leuven, Belgium
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50
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Pratt SJP, Hernández-Ochoa E, Martin SS. Calcium signaling: breast cancer's approach to manipulation of cellular circuitry. Biophys Rev 2020; 12:1343-1359. [PMID: 33569087 PMCID: PMC7755621 DOI: 10.1007/s12551-020-00771-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 10/29/2020] [Indexed: 12/11/2022] Open
Abstract
Calcium is a versatile element that participates in cell signaling for a wide range of cell processes such as death, cell cycle, division, migration, invasion, metabolism, differentiation, autophagy, transcription, and others. Specificity of calcium in each of these processes is achieved through modulation of intracellular calcium concentrations by changing the characteristics (amplitude/frequency modulation) or location (spatial modulation) of the signal. Breast cancer utilizes calcium signaling as an advantage for survival and progression. This review integrates evidence showing that increases in expression of calcium channels, GPCRs, pumps, effectors, and enzymes, as well as resulting intracellular calcium signals, lead to high calcium and/or an elevated calcium- mobilizing capacity necessary for malignant functions such as migratory, invasive, proliferative, tumorigenic, or metastatic capacities.
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Affiliation(s)
- Stephen J P Pratt
- Program in Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD USA.,Department of Physiology, University of Maryland School of Medicine, Baltimore, MD USA.,Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, 655 W. Baltimore Street, Bressler Research Building, Rm 10-020 D, Baltimore, MD 21201 USA
| | - Erick Hernández-Ochoa
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD USA
| | - Stuart S Martin
- Program in Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD USA.,Department of Physiology, University of Maryland School of Medicine, Baltimore, MD USA.,Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, 655 W. Baltimore Street, Bressler Research Building, Rm 10-020 D, Baltimore, MD 21201 USA
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