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Deng M, Zhou Z, Chen J, Li X, Liu Z, Ye J, Wei W, Wang N, Peng Y, Luo X, Jiang L, Zhou F, Zheng X, Liu Z. Enhanced Oxidative Phosphorylation Driven by TACO1 Mitochondrial Translocation Promotes Stemness and Cisplatin Resistance in Bladder Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2408599. [PMID: 39656941 PMCID: PMC11791945 DOI: 10.1002/advs.202408599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/20/2024] [Indexed: 12/17/2024]
Abstract
Chemoresistance poses a critical obstacle in bladder cancer (BCa) treatment, and effective interventions are currently limited. Elevated oxidative phosphorylation (OXPHOS) has been linked to cancer stemness, a determinant of chemoresistance. However, the mechanisms underlying increased OXPHOS during cancer cell chemoresistance remain unclear. This study revealed that the mitochondrial translational activator of cytochrome oxidase subunit 1 (TACO1) is linked to stemness and cisplatin resistance in BCa cells. Mechanistically, mitochondrial TACO1 enhances the translation of the mitochondrial cytochrome c oxidase I (MTCO1), promoting mitochondrial reactive oxygen species (mtROS) by upregulating OXPHOS, consequently driving cancer stemness and cisplatin resistance. Intriguingly, the mitochondrial translocation of TACO1 is mediated by the heat shock protein 90 β (HSP90β), a process that requires circFOXK2 as a scaffold for the TACO1-HSP90β interaction. The mutations at the binding sites of TACO1-circFOXK2-HSP90β disturb the ternary complex and inhibit cancer stemness and cisplatin resistance in BCa cells by suppressing the MTCO1/OXPHOS/mtROS axis. Clinically, BCa patients with increased mitochondrial TACO1 expression respond poorly to cisplatin treatment. This study elucidates the mechanisms by which TACO1 promotes BCa stemness and cisplatin resistance, providing a potential target for mitigating cisplatin resistance for BCa and a biomarker for predicting cisplatin response.
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Affiliation(s)
- Minhua Deng
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐Sen University Cancer CenterGuangzhou510060China
| | - Zhaohui Zhou
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐Sen University Cancer CenterGuangzhou510060China
| | - Jiawei Chen
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐Sen University Cancer CenterGuangzhou510060China
- Department of UrologyShunde HospitalSouthern Medical University (The First People's Hospital of Shunde Foshan)Foshan528000China
| | - Xiangdong Li
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐Sen University Cancer CenterGuangzhou510060China
| | - Zefu Liu
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐Sen University Cancer CenterGuangzhou510060China
| | - Jingwei Ye
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐Sen University Cancer CenterGuangzhou510060China
| | - Wensu Wei
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐Sen University Cancer CenterGuangzhou510060China
| | - Ning Wang
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐Sen University Cancer CenterGuangzhou510060China
| | - Yulu Peng
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐Sen University Cancer CenterGuangzhou510060China
| | - Xin Luo
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐Sen University Cancer CenterGuangzhou510060China
| | - Lijuan Jiang
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐Sen University Cancer CenterGuangzhou510060China
| | - Fangjian Zhou
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐Sen University Cancer CenterGuangzhou510060China
| | - Xianchong Zheng
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐Sen University Cancer CenterGuangzhou510060China
| | - Zhuowei Liu
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐Sen University Cancer CenterGuangzhou510060China
- Department of UrologySun Yat‐sen University Cancer Center Gansu HospitalLanzhou730050China
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Cui M, Yang WM, Yao P. Protective effect of low-dose lactulose in dextran sulfate sodium induced ulcerative colitis model of rats. Sci Rep 2025; 15:2760. [PMID: 39843913 PMCID: PMC11754915 DOI: 10.1038/s41598-025-86823-0] [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: 10/10/2024] [Accepted: 01/14/2025] [Indexed: 01/24/2025] Open
Abstract
Although low-dose lactulose has shown a good theoretical foundation for the treatment of ulcerative colitis (UC) in previous studies, the exact effects and mechanism remain unclear. The rats were randomly distributed into 5 groups, i.e., normal drinking water was provided for an initial 14 days in blank control group, 4% dextran sulfate sodium was used for modeling in the remaining 4 groups. During the 15-24th day, rats in the blank control group were administered with 0.9% saline (0.5 ml/d) by gavage. In the rest 4 groups, rats were administered 0.9% saline (0.5 ml/d, UC model), mesalazine (400 mg/kg/d), lactulose (1000 mg/kg/d), and lactulose + mesalazine (two-drug combination) by gavage. In addition to symptoms and pathological changes, serum IL-6, TNF-α, and High-sensitivity C-reactive protein(Hs-CRP) by ELISA analysis, mRNA and protein expression levels of TLR-2, TLR-4, Nuclear factor-κB(NF-κB), IL-6, and TNF-α in colon tissues by RT-qPCR and WB analyses respectively. Meanwhile, short-chain fatty acid(SCFAs) and intestinal flora were analyzed. Low-dose lactulose improved symptoms (diarrhea, blood in stool, weight loss) and pathological inflammation. In addition to serum IL-6, TNF-α, and Hs-CRP, the mRNA and protein expression levels of TLR-2, TLR-4, NF-κB, IL-6 and TNF-α in the colon were down-regulated with the intervention of lactulose.Meanwhile, lactulose decreased the ileocecal PH, increased SCFAs and altered the intestinal flora. Low-dose lactulose may be beneficial to UC by regulating TLRs/NF-κB pathway, reducing ileocecal PH, increasing SCFAs, regulating intestinal flora and improving the intestinal mucosal barrier. Meanwhile, low-dose lactulose and mesalazine may have additive effects upon combination.
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Affiliation(s)
- Min Cui
- Department of Gastroenterology, The First Affiliated Hospital of Xinjiang Medical University, No.137 LiYuShan Road Xinjiang Province, Urumqi, 830000, China
| | - Wei-Ming Yang
- Xinjiang Medical University, Xinjiang Province, Urumqi, 830000, China
| | - Ping Yao
- Department of Gastroenterology, The First Affiliated Hospital of Xinjiang Medical University, No.137 LiYuShan Road Xinjiang Province, Urumqi, 830000, China.
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Padalko V, Posnik F, Adamczyk M. Mitochondrial Aconitase and Its Contribution to the Pathogenesis of Neurodegenerative Diseases. Int J Mol Sci 2024; 25:9950. [PMID: 39337438 PMCID: PMC11431987 DOI: 10.3390/ijms25189950] [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: 08/06/2024] [Revised: 08/31/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
This survey reviews modern ideas on the structure and functions of mitochondrial and cytosolic aconitase isoenzymes in eukaryotes. Cumulative experimental evidence about mitochondrial aconitases (Aco2) as one of the main targets of reactive oxygen and nitrogen species is generalized. The important role of Aco2 in maintenance of homeostasis of the intracellular iron pool and maintenance of the mitochondrial DNA is discussed. The role of Aco2 in the pathogenesis of some neurodegenerative diseases is highlighted. Inactivation or dysfunction of Aco2 as well as mutations found in the ACO2 gene appear to be significant factors in the development and promotion of various types of neurodegenerative diseases. A restoration of efficient mitochondrial functioning as a source of energy for the cell by targeting Aco2 seems to be one of the promising therapeutic directions to minimize progressive neurodegenerative disorders.
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Affiliation(s)
- Volodymyr Padalko
- Laboratory of Systems and Synthetic Biology, Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
- School of Medicine, V. N. Karazin Kharkiv National University, 61022 Kharkiv, Ukraine
| | - Filip Posnik
- Laboratory of Systems and Synthetic Biology, Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
| | - Malgorzata Adamczyk
- Laboratory of Systems and Synthetic Biology, Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
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Yousefi R, Dennerlein S. Analysis of mitochondrial translation using click chemistry. Methods Enzymol 2024; 706:533-547. [PMID: 39455233 DOI: 10.1016/bs.mie.2024.07.044] [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] [Indexed: 10/28/2024]
Abstract
Mitochondria contain their own gene expression machinery, which synthesizes core subunits of the oxidative phosphorylation system. Monitoring mitochondrial translation within spatial compartments of cells is difficult. Here we describe a method to visualize mitochondrial translation within defined parts of cells, using a click chemistry approach. This method can be applied to different cell types such as neurons and allows detection of newly synthesized mitochondrial proteins in spatial resolution using microscopy techniques. Furthermore, using click chemistry, mitochondrial translation can also be monitored by standard SDS-PAGE. The described method avenues the analysis of newly synthesized mitochondrial encoded proteins in the cellular context, by avoiding the usage of radioactive components.
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Affiliation(s)
- Roya Yousefi
- Institute for Cellular Biochemistry, University Medical Center Goettingen, Goettingen, Germany
| | - Sven Dennerlein
- Institute for Cellular Biochemistry, University Medical Center Goettingen, Goettingen, Germany.
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Haque PS, Kapur N, Barrett TA, Theiss AL. Mitochondrial function and gastrointestinal diseases. Nat Rev Gastroenterol Hepatol 2024; 21:537-555. [PMID: 38740978 PMCID: PMC12036329 DOI: 10.1038/s41575-024-00931-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/10/2024] [Indexed: 05/16/2024]
Abstract
Mitochondria are dynamic organelles that function in cellular energy metabolism, intracellular and extracellular signalling, cellular fate and stress responses. Mitochondria of the intestinal epithelium, the cellular interface between self and enteric microbiota, have emerged as crucial in intestinal health. Mitochondrial dysfunction occurs in gastrointestinal diseases, including inflammatory bowel diseases and colorectal cancer. In this Review, we provide an overview of the current understanding of intestinal epithelial cell mitochondrial metabolism, function and signalling to affect tissue homeostasis, including gut microbiota composition. We also discuss mitochondrial-targeted therapeutics for inflammatory bowel diseases and colorectal cancer and the evolving concept of mitochondrial impairment as a consequence versus initiator of the disease.
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Affiliation(s)
- Parsa S Haque
- Division of Gastroenterology and Hepatology, Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA
| | - Neeraj Kapur
- Department of Medicine, Division of Digestive Diseases and Nutrition, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Terrence A Barrett
- Department of Medicine, Division of Digestive Diseases and Nutrition, University of Kentucky College of Medicine, Lexington, KY, USA
- Lexington Veterans Affairs Medical Center Kentucky, Lexington, KY, USA
| | - Arianne L Theiss
- Division of Gastroenterology and Hepatology, Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA.
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA.
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6
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Park I, Kim KE, Kim J, Kim AK, Bae S, Jung M, Choi J, Mishra PK, Kim TM, Kwak C, Kang MG, Yoo CM, Mun JY, Liu KH, Lee KS, Kim JS, Suh JM, Rhee HW. Mitochondrial matrix RTN4IP1/OPA10 is an oxidoreductase for coenzyme Q synthesis. Nat Chem Biol 2024; 20:221-233. [PMID: 37884807 PMCID: PMC10830421 DOI: 10.1038/s41589-023-01452-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 09/17/2023] [Indexed: 10/28/2023]
Abstract
Targeting proximity-labeling enzymes to specific cellular locations is a viable strategy for profiling subcellular proteomes. Here, we generated transgenic mice (MAX-Tg) expressing a mitochondrial matrix-targeted ascorbate peroxidase. Comparative analysis of matrix proteomes from the muscle tissues showed differential enrichment of mitochondrial proteins. We found that reticulon 4-interacting protein 1 (RTN4IP1), also known as optic atrophy-10, is enriched in the mitochondrial matrix of muscle tissues and is an NADPH oxidoreductase. Interactome analysis and in vitro enzymatic assays revealed an essential role for RTN4IP1 in coenzyme Q (CoQ) biosynthesis by regulating the O-methylation activity of COQ3. Rtn4ip1-knockout myoblasts had markedly decreased CoQ9 levels and impaired cellular respiration. Furthermore, muscle-specific knockdown of dRtn4ip1 in flies resulted in impaired muscle function, which was reversed by dietary supplementation with soluble CoQ. Collectively, these results demonstrate that RTN4IP1 is a mitochondrial NAD(P)H oxidoreductase essential for supporting mitochondrial respiration activity in the muscle tissue.
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Affiliation(s)
- Isaac Park
- Department of Chemistry, Seoul National University, Seoul, Republic of Korea
| | - Kwang-Eun Kim
- Department of Chemistry, Seoul National University, Seoul, Republic of Korea
- Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Jeesoo Kim
- School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
- Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea
| | - Ae-Kyeong Kim
- Metabolism and Neurophysiology Research Group, KRIBB, Daejeon, Republic of Korea
| | - Subin Bae
- BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea
| | - Minkyo Jung
- Neural Circuit Research Group, Korea Brain Research Institute, Daegu, Republic of Korea
| | - Jinhyuk Choi
- Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | | | - Taek-Min Kim
- Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Chulhwan Kwak
- Department of Chemistry, Seoul National University, Seoul, Republic of Korea
| | - Myeong-Gyun Kang
- Department of Chemistry, Seoul National University, Seoul, Republic of Korea
| | - Chang-Mo Yoo
- Department of Chemistry, Seoul National University, Seoul, Republic of Korea
| | - Ji Young Mun
- Neural Circuit Research Group, Korea Brain Research Institute, Daegu, Republic of Korea
| | - Kwang-Hyeon Liu
- BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea
| | - Kyu-Sun Lee
- Metabolism and Neurophysiology Research Group, KRIBB, Daejeon, Republic of Korea.
- School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
| | - Jong-Seo Kim
- School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
- Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea.
| | - Jae Myoung Suh
- Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
| | - Hyun-Woo Rhee
- Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
- School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
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Klemmensen MM, Borrowman SH, Pearce C, Pyles B, Chandra B. Mitochondrial dysfunction in neurodegenerative disorders. Neurotherapeutics 2024; 21:e00292. [PMID: 38241161 PMCID: PMC10903104 DOI: 10.1016/j.neurot.2023.10.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 10/07/2023] [Indexed: 01/21/2024] Open
Abstract
Recent advances in understanding the role of mitochondrial dysfunction in neurodegenerative diseases have expanded the opportunities for neurotherapeutics targeting mitochondria to alleviate symptoms and slow disease progression. In this review, we offer a historical account of advances in mitochondrial biology and neurodegenerative disease. Additionally, we summarize current knowledge of the normal physiology of mitochondria and the pathogenesis of mitochondrial dysfunction, the role of mitochondrial dysfunction in neurodegenerative disease, current therapeutics and recent therapeutic advances, as well as future directions for neurotherapeutics targeting mitochondrial function. A focus is placed on reactive oxygen species and their role in the disruption of telomeres and their effects on the epigenome. The effects of mitochondrial dysfunction in the etiology and progression of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease are discussed in depth. Current clinical trials for mitochondria-targeting neurotherapeutics are discussed.
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Affiliation(s)
- Madelyn M Klemmensen
- University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA 52242, USA
| | - Seth H Borrowman
- Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
| | - Colin Pearce
- Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
| | - Benjamin Pyles
- Aper Funis Research, Union River Innovation Center, Ellsworth, ME 04605, USA
| | - Bharatendu Chandra
- University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA 52242, USA; Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.
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Sun Q, Shi L, Li S, Li J, Zhang R, Huang X, Shao Y, Feng Z, Peng Y, Yang Z, Liu J, Liu H, Long J. PET117 assembly factor stabilizes translation activator TACO1 thereby upregulates mitochondria-encoded cytochrome C oxidase 1 synthesis. Free Radic Biol Med 2023; 205:13-24. [PMID: 37247699 DOI: 10.1016/j.freeradbiomed.2023.05.023] [Citation(s) in RCA: 6] [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: 03/12/2023] [Revised: 05/19/2023] [Accepted: 05/19/2023] [Indexed: 05/31/2023]
Abstract
Cytochrome c oxidase, also known as complex IV, facilitates the transfer of electrons from cytochrome c to molecular oxygen, resulting in the production of ATP. The assembly of complex IV is a tightly regulated and intricate process that entails the coordinated synthesis and integration of subunits encoded by the mitochondria and nucleus into a functional complex. Accurate regulation of translation is crucial for maintaining proper mitochondrial function, and defects in this process can lead to a wide range of mitochondrial disorders and diseases. However, the mechanisms governing mRNA translation by mitoribosomes in mammals remain largely unknown. In this study, we elucidate the critical role of PET117, a chaperone protein involved in complex IV assembly, in the regulation of mitochondria-encoded cytochrome c oxidase 1 (COX1) protein synthesis in human cells. Depletion of PET117 reduced mitochondrial oxygen consumption rate and impaired mitochondrial function. PET117 was found to interact with and stabilize translational activator of COX1 (TACO1) and prevent its ubiquitination. TACO1 overexpression rescued the inhibitory effects on mitochondria caused by PET117 deficiency. These findings provide evidence for a novel PET117-TACO1 axis in the regulation of mitochondrial protein expression, and revealed a previously unknown role of PET117 in human cells.
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Affiliation(s)
- Qiong Sun
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Le Shi
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Shuaijun Li
- School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Jialu Li
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Ruifen Zhang
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Xinghuai Huang
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Yongping Shao
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Zhihui Feng
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Yunhua Peng
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Zhiwei Yang
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Jiankang Liu
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266071, China
| | - Huadong Liu
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266071, China.
| | - Jiangang Long
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China.
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Ren Z, Fan K, Zhen S, Zhang J, Liu Y, Fu J, Qi C, Wei Q, Du Y, Tatar W, Zhang X, Wang G, Rasmusson AG, Wang J, Liu Y. Tetratricopeptide-containing SMALL KERNEL 11 is essential for the assembly of cytochrome c oxidase in maize mitochondria. PLANT PHYSIOLOGY 2023; 192:170-187. [PMID: 36722259 DOI: 10.1093/plphys/kiad062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/13/2022] [Accepted: 01/02/2023] [Indexed: 05/03/2023]
Abstract
Assembly of the functional complexes of the mitochondrial respiratory chain requires sophisticated and efficient regulatory mechanisms. In plants, the subunit composition and assembly factors involved in the biogenesis of cytochrome c oxidase (complex IV) are substantially less defined than in mammals and yeast. In this study, we cloned maize (Zea mays) Small kernel 11 (Smk11) via map-based cloning. Smk11 encodes a mitochondria-localized tetratricopeptide repeat protein. Disruption of Smk11 severely affected the assembly and activity of mitochondrial complex IV, leading to delayed plant growth and seed development. Protein interactions studies revealed that SMK11 might interact with four putative complex IV assembly factors, Inner membrane peptidase 1A (ZmIMP1A), MYB domain protein 3R3 (ZmMYB3R-3), cytochrome c oxidase 23 (ZmCOX23), and mitochondrial ferredoxin 1 (ZmMFDX1), among which ZmMFDX1 might interact with subunits ZmCOX6a and ZmCOX-X1; ZmMYB3R-3 might also interact with ZmCOX6a. The mutation of SMK11 perturbed the normal assembly of these subunits, leading to the inactivation of complex IV. The results of this study revealed that SMK11 serves as an accessory assembly factor required for the normal assembly of subunits into complex IV, which will accelerate the elucidation of the assembly of complex IV in plant mitochondria.
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Affiliation(s)
- Zhenjing Ren
- Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Kaijian Fan
- Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Sihan Zhen
- College of Agronomy and Biotechnology, China Agricultural University, Beijing 100094, China
| | - Jie Zhang
- College of Agronomy and Biotechnology, China Agricultural University, Beijing 100094, China
| | - Yan Liu
- Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Junjie Fu
- Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Chunlai Qi
- Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Qianhan Wei
- College of Agronomy and Biotechnology, China Agricultural University, Beijing 100094, China
| | - Yao Du
- College of Agronomy and Biotechnology, China Agricultural University, Beijing 100094, China
| | - Wurinile Tatar
- Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Xiaofeng Zhang
- Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Guoying Wang
- Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | | | - Jianhua Wang
- College of Agronomy and Biotechnology, China Agricultural University, Beijing 100094, China
| | - Yunjun Liu
- Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China
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10
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Anitha A, Thanseem I, Iype M, Thomas SV. Mitochondrial dysfunction in cognitive neurodevelopmental disorders: Cause or effect? Mitochondrion 2023; 69:18-32. [PMID: 36621534 DOI: 10.1016/j.mito.2023.01.002] [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: 09/24/2022] [Revised: 12/21/2022] [Accepted: 01/04/2023] [Indexed: 01/07/2023]
Abstract
Mitochondria have a crucial role in brain development and neurogenesis, both in embryonic and adult brains. Since the brain is the highest energy consuming organ, it is highly vulnerable to mitochondrial dysfunction. This has been implicated in a range of brain disorders including, neurodevelopmental conditions, psychiatric illnesses, and neurodegenerative diseases. Genetic variations in mitochondrial DNA (mtDNA), and nuclear DNA encoding mitochondrial proteins, have been associated with several cognitive disorders. However, it is not yet clear whether mitochondrial dysfunction is a primary cause of these conditions or a secondary effect. Our review article deals with this topic, and brings out recent advances in mitochondria-oriented therapies. Mitochondrial dysfunction could be involved in the pathogenesis of a subset of disorders involving cognitive impairment. In these patients, mitochondrial dysfunction could be the cause of the condition, rather than the consequence. There are vast areas in this topic that remains to be explored and elucidated.
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Affiliation(s)
- Ayyappan Anitha
- Dept. of Neurogenetics, Institute for Communicative and Cognitive Neurosciences (ICCONS), Shoranur, Palakkad 679 523, Kerala, India.
| | - Ismail Thanseem
- Dept. of Neurogenetics, Institute for Communicative and Cognitive Neurosciences (ICCONS), Shoranur, Palakkad 679 523, Kerala, India
| | - Mary Iype
- Dept. of Pediatric Neurology, Government Medical College, Thiruvananthapuram 695 011, Kerala, India; Dept. of Neurology, ICCONS, Thiruvananthapuram 695 033, Kerala, India
| | - Sanjeev V Thomas
- Dept. of Neurology, ICCONS, Thiruvananthapuram 695 033, Kerala, India
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11
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Angeloni C, Malaguti M, Prata C, Freschi M, Barbalace MC, Hrelia S. Mechanisms Underlying Neurodegenerative Disorders and Potential Neuroprotective Activity of Agrifood By-Products. Antioxidants (Basel) 2022; 12:94. [PMID: 36670956 PMCID: PMC9854890 DOI: 10.3390/antiox12010094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/23/2022] [Accepted: 12/25/2022] [Indexed: 01/03/2023] Open
Abstract
Neurodegenerative diseases, characterized by progressive loss in selected areas of the nervous system, are becoming increasingly prevalent worldwide due to an aging population. Despite their diverse clinical manifestations, neurodegenerative diseases are multifactorial disorders with standard features and mechanisms such as abnormal protein aggregation, mitochondrial dysfunction, oxidative stress and inflammation. As there are no effective treatments to counteract neurodegenerative diseases, increasing interest has been directed to the potential neuroprotective activities of plant-derived compounds found abundantly in food and in agrifood by-products. Food waste has an extremely negative impact on the environment, and recycling is needed to promote their disposal and overcome this problem. Many studies have been carried out to develop green and effective strategies to extract bioactive compounds from food by-products, such as peel, leaves, seeds, bran, kernel, pomace, and oil cake, and to investigate their biological activity. In this review, we focused on the potential neuroprotective activity of agrifood wastes obtained by common products widely produced and consumed in Italy, such as grapes, coffee, tomatoes, olives, chestnuts, onions, apples, and pomegranates.
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Affiliation(s)
- Cristina Angeloni
- Department for Life Quality Studies, Alma Mater Studiorum–University of Bologna, Corso D’Augusto 237, 47921 Rimini, Italy
| | - Marco Malaguti
- Department for Life Quality Studies, Alma Mater Studiorum–University of Bologna, Corso D’Augusto 237, 47921 Rimini, Italy
| | - Cecilia Prata
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum–University of Bologna, Via Irnerio 48, 40126 Bologna, Italy
| | - Michela Freschi
- Department for Life Quality Studies, Alma Mater Studiorum–University of Bologna, Corso D’Augusto 237, 47921 Rimini, Italy
| | - Maria Cristina Barbalace
- Department for Life Quality Studies, Alma Mater Studiorum–University of Bologna, Corso D’Augusto 237, 47921 Rimini, Italy
| | - Silvana Hrelia
- Department for Life Quality Studies, Alma Mater Studiorum–University of Bologna, Corso D’Augusto 237, 47921 Rimini, Italy
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12
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Lima DDD, Cyrino LAR, Ferreira GK, Magro DDD, Calegari CR, Cabral H, Cavichioli N, Ramos SA, Ullmann OM, Mayer Y, Pscheidt LC, Schramm MA, Tomasi MC, Stammerjohann FLS, Delmonego L, Packer MH, Fiamoncini H. Neuroinflammation and neuroprogression produced by oxidative stress in euthymic bipolar patients with different onset disease times. Sci Rep 2022; 12:16742. [PMID: 36202963 PMCID: PMC9537234 DOI: 10.1038/s41598-022-21170-y] [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: 01/01/2022] [Accepted: 09/23/2022] [Indexed: 11/17/2022] Open
Abstract
Bipolar disorder (BD) is associated with systemic toxicity, represented by changes in biomarkers associated with mood episodes, leading to neurological damage, which may reflect cognitive functions and functionality and the progression of the disease. We aimed to analyze the effect of four biomarkers, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and thiobarbituric acid reactive substances (TBA-RS), related to oxidative stress in BD and to correlate them with cognitive functions and functionality. We studied 50 bipolar types I/II patients in the euthymic phase, which was divided into two subgroups with 25 patients each (≤ 3 years and ≥ 10 years of diagnosis, from the first episode of mania) and 25 control patients. To analyze frontal cognitive functions and functionality, we used the Frontal Assessment Battery (FAB) and Functioning Assessment Short Test (FAST) tests, respectively. The scores of the FAST and FAB tests showed an increase and decrease respectively, in both bipolar groups, when compared to the control group, demonstrating impairment in cognitive functions and functionality since the disease onset. In addition, changes occurred in all six domains of the FAST test, and in four domains of the FAB test in bipolar patients when compared to the control group. Regarding oxidative stress biomarkers, we did not find changes in SOD and GSH-Px activities; however, a significant increase in CAT activity and lipid peroxidation was observed in both groups, although the patients were euthymic and medicated. These results allow us to raise the hypothesis that since the beginning of the disease, the euthymic bipolar patient has presented a level of oxidative stress, which gets worse with the evolution of the disease, promoting impairments in the frontal cognitive functions and functionality gradually.
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Affiliation(s)
- Daniela Delwing-de Lima
- Programa de Pós-Graduação Em Saúde E Meio Ambiente, Universidade da Região de Joinville- UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, SC, CEP 89201-972, Brasil.,Departamento de Medicina, Universidade da Região de Joinville UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, SC, CEP 89201-972, Brasil
| | - Luiz Arthur Rangel Cyrino
- Programa de Pós-Graduação Em Saúde E Meio Ambiente, Universidade da Região de Joinville- UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, SC, CEP 89201-972, Brasil. .,Departamento de Farmácia, Universidade da Região de Joinville UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, Joinville, SC, CEP 89201-972, Brasil. .,Departamento de Psicologia, Universidade da Região de Joinville UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, Joinville, SC, CEP 89201-972, Brasil.
| | - Gabriela Kozuchovski Ferreira
- Programa de Pós-Graduação Em Ciência E Engenharia de Materiais, Universidade Sociedade Educacional de Santa Catarina UNISOCIESC, Joinville, Santa Catarina, Brasil
| | - Débora Delwing Dal Magro
- Departamento de Ciências Naturais, Centro de Ciências Exatas E Naturais, Universidade Regional de Blumenau, Rua Antônio da Veiga, 140, Blumenau, SC, CEP 89012-900, Brasil
| | - Claudia Regina Calegari
- Departamento de Psicologia, Universidad Europea del Atlántico, UNEATLANTICO, Calle Isabel Torres, 21, Santander, Spain
| | - Heloisi Cabral
- Departamento de Ciências Biológicas, Universidade da Região de Joinville UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, SC CEP, CEP 89201-972, Brasil
| | - Natalia Cavichioli
- Departamento de Biomedicina, Centro de Ciências da Saúde, Universidade Regional de Blumenau, Rua Antônio da Veiga, 140, Blumenau, SC, CEP 89012-900, Brasil
| | - Silvia Aparecida Ramos
- Departamento de Farmácia, Universidade da Região de Joinville UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, Joinville, SC, CEP 89201-972, Brasil
| | - Oliver Matheus Ullmann
- Departamento de Farmácia, Universidade da Região de Joinville UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, Joinville, SC, CEP 89201-972, Brasil
| | - Yasmin Mayer
- Departamento de Farmácia, Universidade da Região de Joinville UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, Joinville, SC, CEP 89201-972, Brasil
| | - Luana Carla Pscheidt
- Departamento de Farmácia, Universidade da Região de Joinville UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, Joinville, SC, CEP 89201-972, Brasil
| | - Maria Augusta Schramm
- Departamento de Farmácia, Universidade da Região de Joinville UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, Joinville, SC, CEP 89201-972, Brasil
| | - Maria Cecília Tomasi
- Departamento de Psicologia, Universidade da Região de Joinville UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, Joinville, SC, CEP 89201-972, Brasil
| | - Felipe Luis Schmoller Stammerjohann
- Departamento de Psicologia, Universidade da Região de Joinville UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, Joinville, SC, CEP 89201-972, Brasil
| | - Larissa Delmonego
- Departamento de Medicina, Universidade da Região de Joinville UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, SC, CEP 89201-972, Brasil
| | - Maria Helena Packer
- Programa de Pós-Graduação Em Saúde E Meio Ambiente, Universidade da Região de Joinville- UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, SC, CEP 89201-972, Brasil
| | - Heloiza Fiamoncini
- Programa de Pós-Graduação Em Saúde E Meio Ambiente, Universidade da Região de Joinville- UNIVILLE, Rua Paulo Malschitzki, 10 - Zona Industrial Norte, Joinville, SC, CEP 89201-972, Brasil
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13
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Wu XH, Lin SZ, Zhou YQ, Wang WQ, Li JY, Chen QD. VARS2 gene mutation leading to overall developmental delay in a child with epilepsy: A case report. World J Clin Cases 2022; 10:8749-8754. [PMID: 36157797 PMCID: PMC9453344 DOI: 10.12998/wjcc.v10.i24.8749] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 07/02/2022] [Accepted: 07/22/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The mitochondrial respiratory chain defects have become the most common cause of neurometabolic disorders in children and adults, which can occur at any time in life, often associated with neurological dysfunction, and lead to chronic disability and premature death. Approximately one-third of patients with mitochondrial disease have biochemical defects involving multiple respiratory chain complexes, suggesting defects in protein synthesis within the mitochondria. We here report a child with VARS2 gene mutations causing mitochondrial disease.
CASE SUMMARY A girl, aged 3 years and 4 mo, had been unable to sit and crawl alone since birth, with obvious seizures and microcephaly. Brain magnetic resonance imaging showed symmetrical, flaky, long T1-weighted and low T2-weighted signals in the posterior part of the bilateral putamen with a high signal shadow. T2 fluid-attenuated inversion recovery imaging showed a slightly high signal and diffusion-weighted imaging showed an obvious high signal. Whole-exome gene sequencing revealed a compound heterozygous mutation in the VARS2 gene, c.1163(exon11)C>T and c.1940(exon20)C>T, which was derived from the parents. The child was diagnosed with combined oxidative phosphorylation deficiency type 20.
CONCLUSION In this patient, mitochondrial disorders including Leigh syndrome and MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) were ruled out, and combined oxidative phosphorylation deficiency type 20 was diagnosed, expanding the phenotypic spectrum of the disease.
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Affiliation(s)
- Xiao-Hui Wu
- Department of Neurology, Quanzhou Children's Hospital, Quanzhou 362000, Fujian Province, China
| | - Shuang-Zhu Lin
- Diagnosis and Treatment Center for Children, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun 130103, Jilin Province, China
| | - Yan-Qiu Zhou
- Diagnosis and Treatment Center for Children, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun 130103, Jilin Province, China
| | - Wan-Qi Wang
- Pediatrics of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, Jilin province, China
| | - Jia-Yi Li
- Pediatrics of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, Jilin province, China
| | - Qian-Dui Chen
- College of Integrated Chinese and Western Medicine, Changchun University of Chinese Medicine, Changchun 130117, Jilin Province, China
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14
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Li P, Guo D, Zhang X, Ji K, Lv H, Zhang Y, Chen Z, Ma J, Fang Y, Liu Y. Compound Heterozygous COX20 Variants Impair the Function of Mitochondrial Complex IV to Cause a Syndrome Involving Ophthalmoplegia and Visual Failure. Front Neurol 2022; 13:873943. [PMID: 35651336 PMCID: PMC9149563 DOI: 10.3389/fneur.2022.873943] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/06/2022] [Indexed: 11/13/2022] Open
Abstract
The cytochrome c oxidase 20 (COX20) gene encodes a protein with a crucial role in the assembly of mitochondrial complex IV (CIV). Mutations in this gene can result in ataxia and muscle hypotonia. However, ophthalmoplegia and visual failure associated with COX20 mutation have not been examined previously. Moreover, the mechanism causing the phenotype of patients with COX20 variants to differ from that of patients with mutations in other genes impairing CIV assembly is unclear. In this investigation, the aim was to assess the relation between COX20 variants and CIV assembly. We performed detailed clinical, physical, and biochemical investigations of affected individuals. Western blotting, reverse transcription-polymerase chain reaction, and blue native-polyacrylamide gel electrophoresis were used to analyze the expression level of COX20 and oxidative phosphorylation. A Seahorse XF Cell Mito Stress Test and enzymatic activity analysis were performed to evaluate mitochondrial function. Whole-exome sequencing revealed the same compound heterozygous mutations (c.41A > G and c.222G > T, NM_198076) in COX20 in two siblings. This is the first description of ophthalmoplegia and visual failure associated with COX20 variants. In vitro analysis confirmed that the COX20 protein level was significantly decreased, impairing the assembly and activity of CIV in patients' fibroblast. Overexpression of COX20 using a transduced adenovirus partially restored the function of the patients' fibroblasts. Early-onset complex movement disorders may be closely related to COX20 variants. Our results broaden the clinical phenotypes of patients with COX20 variants showing ophthalmoplegia and visual failure. Additionally, dysfunction of COX20 protein can impair the assembly and activity of CIV.
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Affiliation(s)
- Peizheng Li
- Department of Neurology, Qilu Hospital, Shandong University, Jinan, China
| | - Dandan Guo
- Department of Neurology, Qilu Hospital, Shandong University, Jinan, China
| | - Xiufang Zhang
- Department of Neurology, Qilu Hospital, Shandong University, Jinan, China
| | - Kunqian Ji
- Department of Neurology, Qilu Hospital, Shandong University, Jinan, China
| | - Hongbo Lv
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yanli Zhang
- Department of Neurology, Heze Municipal Hospital, Heze, China
| | - Zhichao Chen
- Department of Neurology, Qilu Hospital, Shandong University, Jinan, China
| | - Jun Ma
- Department of Neurology, Qilu Hospital, Shandong University, Jinan, China
| | - Yaofeng Fang
- Department of Neurology, Qilu Hospital, Shandong University, Jinan, China
| | - Yiming Liu
- Department of Neurology, Qilu Hospital, Shandong University, Jinan, China
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15
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Chai CH, Hong CF, Huang JW. Identification and Characterization of a Multifunctional Biocontrol Agent, Streptomyces griseorubiginosus LJS06, Against Cucumber Anthracnose. Front Microbiol 2022; 13:923276. [PMID: 35722317 PMCID: PMC9201727 DOI: 10.3389/fmicb.2022.923276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 05/16/2022] [Indexed: 11/29/2022] Open
Abstract
Twenty-eight bacterial strains isolated from Chinese herb extracts, beer fermentation waste, and raw oyster shells were evaluated for their efficacy in controlling cucumber anthracnose. Four bacterial strains, namely TG01, TG02, LJS06, and LJS08, were found to effectively reduce the mycelial growth of Colletotrichum orbiculare COC3 on PDA media. Spraying or drenching LJS06 spore suspension before inoculation significantly p < 0.05 reduced disease severity; thus, LJS06 was subject to further characterization. On the basis of the morphological, physiological, and biochemical characteristics and a multilocus sequence analysis of partial 16S rRNA, atpD, rpoB, and trpB genes, LJS06 was identified to be Streptomyces griseorubiginosus (Ryabova and Preobrazhenskaya) Pridham et al. Physiological and biochemical tests revealed that S. griseorubiginosus LJS06 can produce amylase, cellulase, chitinase, protease, siderophore, polyamines, and indole-3-acetic acid. Thus, a culture filtrate of LJS06 (specifically SL06) was formulated and evaluated for its efficacy against conidial germination, appressorium formation, and anthracnose management. Diluted SL06 was found to significantly (p < 0.05) inhibit conidial germination and appressorium formation, which can be attributed to impaired membrane integrity, accumulated reactive oxygen species (ROS), and impaired energy metabolism in the conidia. In addition, the spraying and drenching of diluted SL06 before inoculation consistently and significantly (p < 0.05) reduced anthracnose severity. These results jointly suggest that S. griseorubiginosus LJS06 can aid in the management of cucumber anthracnose by directly inhibiting conidial function and priming the plant defense system.
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Affiliation(s)
- Chien Hao Chai
- Department of Plant Pathology, National Chung Hsing University, Taichung, Taiwan
| | - Cheng-Fang Hong
- Department of Plant Pathology, National Chung Hsing University, Taichung, Taiwan
- Innovative and Development Center of Sustainable Agriculture, National Chung Hsing University, Taichung, Taiwan
- *Correspondence: Cheng-Fang Hong,
| | - Jenn-Wen Huang
- Department of Plant Pathology, National Chung Hsing University, Taichung, Taiwan
- Innovative and Development Center of Sustainable Agriculture, National Chung Hsing University, Taichung, Taiwan
- Jenn-Wen Huang,
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16
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Qin Y, Wang X, Yan X, Zhu D, Wang J, Chen S, Wang S, Wen Y, Martyniuk CJ, Zhao Y. Developmental toxicity of fenbuconazole in zebrafish: effects on mitochondrial respiration and locomotor behavior. Toxicology 2022; 470:153137. [PMID: 35218879 DOI: 10.1016/j.tox.2022.153137] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 02/17/2022] [Accepted: 02/22/2022] [Indexed: 01/10/2023]
Abstract
Triazole fungicides are used to control the disease of cereal crops but may also cause adverse effects on non-target organisms. There is a lack of toxicity data for some triazoles such as fenbuconazole in aquatic organisms. This research was conducted to evaluate the toxicity of fenbuconazole at environmentally relevant concentrations with attention on the mitochondria, antioxidant system, and locomotor activity in zebrafish. Zebrafish were exposed to one concentration of 5, 50, 200 or 500ng/L fenbuconazole for 96h. There was no effect on survival nor percentage of fish hatched, but exposure to 200 and 500ng/L fenbuconazole resulted in malformation and hypoactivity in zebrafish. Oxygen consumption rates (OCR) of embryos were measured to determine if the fungicide impaired mitochondrial respiration. Exposure to 500ng/L fenbuconazole reduced basal OCR and oligomycin-induced ATP linked respiration in exposed fish. Fenbuconazole reduced mitochondrial membrane potential and reduced the activities of mitochondrial Complex II and III. Transcript levels of both sdhc and cyc1, each related to Complex II and III, were also altered in expression by fenbuconazole exposure, consistent with mitochondrial dysfunction in embryos. Fenbuconazole activated the antioxidant system, based upon both transcriptional and enzymatic data in zebrafish. Consistent with mitochondrial impairment, molecular docking confirmed a strong binding capacity of the fungicide at the Qi site of Complex III, revealing this complex is susceptible to fenbuconazole. This study reveals potential toxicity pathways related to fenbuconazole exposure in aquatic organisms; such data can improve risk assessments for triazole fungicides.
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Affiliation(s)
- Yingju Qin
- Institute of Environmental Research at Greater Bay Area; Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Guangzhou University, Guangzhou 510006, China
| | - Xiaohong Wang
- Institute of Environmental Research at Greater Bay Area; Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Guangzhou University, Guangzhou 510006, China.
| | - Xiliang Yan
- Institute of Environmental Research at Greater Bay Area; Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Guangzhou University, Guangzhou 510006, China.
| | - Di Zhu
- State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration, School of Environment, Northeast Normal University, Changchun, Jilin 130117, P. R. China
| | - Jia Wang
- State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration, School of Environment, Northeast Normal University, Changchun, Jilin 130117, P. R. China
| | - Siying Chen
- Institute of Environmental Research at Greater Bay Area; Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Guangzhou University, Guangzhou 510006, China
| | - Shuo Wang
- State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration, School of Environment, Northeast Normal University, Changchun, Jilin 130117, P. R. China
| | - Yang Wen
- Key Laboratory of Environmental Materials and Pollution Control, The Education Department of Jilin Province, School of Environmental Science and Engineering, Jilin Normal University, Siping, Jilin 136000, PR China
| | - Christopher J Martyniuk
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, UF Genetics Institute, Interdisciplinary Program in Biomedical Sciences in Neuroscience, University of Florida, Gainesville, Florida, 32611, USA
| | - Yuanhui Zhao
- State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration, School of Environment, Northeast Normal University, Changchun, Jilin 130117, P. R. China.
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17
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Vercellino I, Sazanov LA. The assembly, regulation and function of the mitochondrial respiratory chain. Nat Rev Mol Cell Biol 2022; 23:141-161. [PMID: 34621061 DOI: 10.1038/s41580-021-00415-0] [Citation(s) in RCA: 453] [Impact Index Per Article: 151.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2021] [Indexed: 02/08/2023]
Abstract
The mitochondrial oxidative phosphorylation system is central to cellular metabolism. It comprises five enzymatic complexes and two mobile electron carriers that work in a mitochondrial respiratory chain. By coupling the oxidation of reducing equivalents coming into mitochondria to the generation and subsequent dissipation of a proton gradient across the inner mitochondrial membrane, this electron transport chain drives the production of ATP, which is then used as a primary energy carrier in virtually all cellular processes. Minimal perturbations of the respiratory chain activity are linked to diseases; therefore, it is necessary to understand how these complexes are assembled and regulated and how they function. In this Review, we outline the latest assembly models for each individual complex, and we also highlight the recent discoveries indicating that the formation of larger assemblies, known as respiratory supercomplexes, originates from the association of the intermediates of individual complexes. We then discuss how recent cryo-electron microscopy structures have been key to answering open questions on the function of the electron transport chain in mitochondrial respiration and how supercomplexes and other factors, including metabolites, can regulate the activity of the single complexes. When relevant, we discuss how these mechanisms contribute to physiology and outline their deregulation in human diseases.
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Affiliation(s)
- Irene Vercellino
- Institute of Science and Technology Austria, Klosterneuburg, Austria
| | - Leonid A Sazanov
- Institute of Science and Technology Austria, Klosterneuburg, Austria.
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18
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Vidali S, Gerlini R, Thompson K, Urquhart JE, Meisterknecht J, Aguilar‐Pimentel JA, Amarie OV, Becker L, Breen C, Calzada‐Wack J, Chhabra NF, Cho Y, da Silva‐Buttkus P, Feichtinger RG, Gampe K, Garrett L, Hoefig KP, Hölter SM, Jameson E, Klein‐Rodewald T, Leuchtenberger S, Marschall S, Mayer‐Kuckuk P, Miller G, Oestereicher MA, Pfannes K, Rathkolb B, Rozman J, Sanders C, Spielmann N, Stoeger C, Szibor M, Treise I, Walter JH, Wurst W, Mayr JA, Fuchs H, Gärtner U, Wittig I, Taylor RW, Newman WG, Prokisch H, Gailus‐Durner V, Hrabě de Angelis M. Characterising a homozygous two-exon deletion in UQCRH: comparing human and mouse phenotypes. EMBO Mol Med 2021; 13:e14397. [PMID: 34750991 PMCID: PMC8649870 DOI: 10.15252/emmm.202114397] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 10/06/2021] [Accepted: 10/07/2021] [Indexed: 12/27/2022] Open
Abstract
Mitochondrial disorders are clinically and genetically diverse, with isolated complex III (CIII) deficiency being relatively rare. Here, we describe two affected cousins, presenting with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. Genetic investigations in both cases identified a homozygous deletion of exons 2 and 3 of UQCRH, which encodes a structural complex III (CIII) subunit. We generated a mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh-/- ), which also presented with lactic acidosis and hyperammonaemia, but had a more severe, non-episodic phenotype, resulting in failure to thrive and early death. The biochemical phenotypes observed in patient and Uqcrh-/- mouse tissues were remarkably similar, displaying impaired CIII activity, decreased molecular weight of fully assembled holoenzyme and an increase of an unexpected large supercomplex (SXL ), comprising mostly of one complex I (CI) dimer and one CIII dimer. This phenotypic similarity along with lentiviral rescue experiments in patient fibroblasts verifies the pathogenicity of the shared genetic defect, demonstrating that the Uqcrh-/- mouse is a valuable model for future studies of human CIII deficiency.
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19
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Salvia miltiorrhiza Protects Endothelial Dysfunction against Mitochondrial Oxidative Stress. Life (Basel) 2021; 11:life11111257. [PMID: 34833133 PMCID: PMC8622679 DOI: 10.3390/life11111257] [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: 10/19/2021] [Revised: 11/05/2021] [Accepted: 11/16/2021] [Indexed: 11/23/2022] Open
Abstract
Salvia miltiorrhiza (SM) is a common traditional Chinese medicine used in the treatment of cardiovascular and cerebrovascular diseases. Endothelial dysfunction plays an important role in the pathology of cardiovascular diseases. Endothelial dysfunction may induce inflammation and change vascular tone and permeability. The main pathological mechanism of endothelial dysfunction is the formation of reactive oxygen species (ROS). Mitochondria are the main source of energy and can also produce large amounts of ROS. Recent studies have shown that extracts of SM have antioxidative, anti-inflammatory, and antithrombus properties. In this review, we discuss the mechanism of oxidative stress in the mitochondria, endothelial dysfunction, and the role of SM in these oxidative events.
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20
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Wang X, Zhou S, Wu X, Wei Q, Shang Y, Sun G, Mei X, Dong Y, Sha W, Zhang H. High-altitude adaptation in vertebrates as revealed by mitochondrial genome analyses. Ecol Evol 2021; 11:15077-15084. [PMID: 34765161 PMCID: PMC8571627 DOI: 10.1002/ece3.8189] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 09/09/2021] [Accepted: 09/13/2021] [Indexed: 12/25/2022] Open
Abstract
The high-altitude environment may drive vertebrate evolution in a certain way, and vertebrates living in different altitude environments might have different energy requirements. We hypothesized that the high-altitude environment might impose different influences on vertebrate mitochondrial genomes (mtDNA). We used selection pressure analyses and PIC (phylogenetic independent contrasts) analysis to detect the evolutionary rate of vertebrate mtDNA protein-coding genes (PCGs) from different altitudes. The results showed that the ratio of nonsynonymous/synonymous substitutions (dN/dS) in the mtDNA PCGs was significantly higher in high-altitude vertebrates than in low-altitude vertebrates. The seven rapidly evolving genes were shared by the high-altitude vertebrates, and only one positive selection gene (ND5 gene) was detected in the high-altitude vertebrates. Our results suggest the mtDNA evolutionary rate in high-altitude vertebrates was higher than in low-altitude vertebrates as their evolution requires more energy in a high-altitude environment. Our study demonstrates the high-altitude environment (low atmospheric O2 levels) drives vertebrate evolution in mtDNA PCGs.
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Affiliation(s)
- Xibao Wang
- College of Life ScienceQufu Normal UniversityQufuChina
| | | | - Xiaoyang Wu
- College of Life ScienceQufu Normal UniversityQufuChina
| | - Qinguo Wei
- College of Life ScienceQufu Normal UniversityQufuChina
| | | | - Guolei Sun
- College of Life ScienceQufu Normal UniversityQufuChina
| | - Xuesong Mei
- College of Life ScienceQufu Normal UniversityQufuChina
| | - Yuehuan Dong
- College of Life ScienceQufu Normal UniversityQufuChina
| | - Weilai Sha
- College of Life ScienceQufu Normal UniversityQufuChina
| | - Honghai Zhang
- College of Life ScienceQufu Normal UniversityQufuChina
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21
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Mitochondria and Antibiotics: For Good or for Evil? Biomolecules 2021; 11:biom11071050. [PMID: 34356674 PMCID: PMC8301944 DOI: 10.3390/biom11071050] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/12/2021] [Accepted: 07/15/2021] [Indexed: 01/16/2023] Open
Abstract
The discovery and application of antibiotics in the common clinical practice has undeniably been one of the major medical advances in our times. Their use meant a drastic drop in infectious diseases-related mortality and contributed to prolonging human life expectancy worldwide. Nevertheless, antibiotics are considered by many a double-edged sword. Their extensive use in the past few years has given rise to a global problem: antibiotic resistance. This factor and the increasing evidence that a wide range of antibiotics can damage mammalian mitochondria, have driven a significant sector of the medical and scientific communities to advise against the use of antibiotics for purposes other to treating severe infections. Notwithstanding, a notorious number of recent studies support the use of these drugs to treat very diverse conditions, ranging from cancer to neurodegenerative or mitochondrial diseases. In this context, there is great controversy on whether the risks associated to antibiotics outweigh their promising beneficial features. The aim of this review is to provide insight in the topic, purpose for which the most relevant findings regarding antibiotic therapies have been discussed.
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22
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Gonzalez-Franquesa A, Stocks B, Chubanava S, Hattel HB, Moreno-Justicia R, Peijs L, Treebak JT, Zierath JR, Deshmukh AS. Mass-spectrometry-based proteomics reveals mitochondrial supercomplexome plasticity. Cell Rep 2021; 35:109180. [PMID: 34038727 DOI: 10.1016/j.celrep.2021.109180] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 01/29/2021] [Accepted: 05/04/2021] [Indexed: 11/26/2022] Open
Abstract
Mitochondrial respiratory complex subunits assemble in supercomplexes. Studies of supercomplexes have typically relied upon antibody-based quantification, often limited to a single subunit per respiratory complex. To provide a deeper insight into mitochondrial and supercomplex plasticity, we combine native electrophoresis and mass spectrometry to determine the supercomplexome of skeletal muscle from sedentary and exercise-trained mice. We quantify 422 mitochondrial proteins within 10 supercomplex bands in which we show the debated presence of complexes II and V. Exercise-induced mitochondrial biogenesis results in non-stoichiometric changes in subunits and incorporation into supercomplexes. We uncover the dynamics of supercomplex-related assembly proteins and mtDNA-encoded subunits after exercise. Furthermore, exercise affects the complexing of Lactb, an obesity-associated mitochondrial protein, and ubiquinone biosynthesis proteins. Knockdown of ubiquinone biosynthesis proteins leads to alterations in mitochondrial respiration. Our approach can be applied to broad biological systems. In this instance, comprehensively analyzing respiratory supercomplexes illuminates previously undetectable complexity in mitochondrial plasticity.
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Affiliation(s)
- Alba Gonzalez-Franquesa
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Ben Stocks
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Sabina Chubanava
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Helle B Hattel
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Roger Moreno-Justicia
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Lone Peijs
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Jonas T Treebak
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Juleen R Zierath
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17177, Sweden
| | - Atul S Deshmukh
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen 2200, Denmark.
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23
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Chen Z, Xia Y, Liu H, Liu H, Xun L. The Mechanisms of Thiosulfate Toxicity against Saccharomyces cerevisiae. Antioxidants (Basel) 2021; 10:antiox10050646. [PMID: 33922196 PMCID: PMC8146336 DOI: 10.3390/antiox10050646] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/09/2021] [Accepted: 04/16/2021] [Indexed: 11/16/2022] Open
Abstract
Elemental sulfur and sulfite have been used to inhibit the growth of yeasts, but thiosulfate has not been reported to be toxic to yeasts. We observed that thiosulfate was more inhibitory than sulfite to Saccharomyces cerevisiae growing in a common yeast medium. At pH < 4, thiosulfate was a source of elemental sulfur and sulfurous acid, and both were highly toxic to the yeast. At pH 6, thiosulfate directly inhibited the electron transport chain in yeast mitochondria, leading to reductions in oxygen consumption, mitochondrial membrane potential and cellular ATP. Although thiosulfate was converted to sulfite and H2S by the mitochondrial rhodanese Rdl1, its toxicity was not due to H2S as the rdl1-deletion mutant that produced significantly less H2S was more sensitive to thiosulfate than the wild type. Evidence suggests that thiosulfate inhibits cytochrome c oxidase of the electron transport chain in yeast mitochondria. Thus, thiosulfate is a potential agent against yeasts.
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Affiliation(s)
- Zhigang Chen
- State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Road, Qingdao 266237, China; (Z.C.); (Y.X.); (H.L.)
| | - Yongzhen Xia
- State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Road, Qingdao 266237, China; (Z.C.); (Y.X.); (H.L.)
| | - Huaiwei Liu
- State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Road, Qingdao 266237, China; (Z.C.); (Y.X.); (H.L.)
| | - Honglei Liu
- State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Road, Qingdao 266237, China; (Z.C.); (Y.X.); (H.L.)
- Correspondence: (H.L.); (L.X.); Tel.: +86-15966642788 (H.L.); +1-509-335-2787 (L.X.)
| | - Luying Xun
- State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Road, Qingdao 266237, China; (Z.C.); (Y.X.); (H.L.)
- School of Molecular Biosciences, Washington State University, Pullman, WA 991647520, USA
- Correspondence: (H.L.); (L.X.); Tel.: +86-15966642788 (H.L.); +1-509-335-2787 (L.X.)
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24
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Ullah H, Di Minno A, Santarcangelo C, Khan H, Daglia M. Improvement of Oxidative Stress and Mitochondrial Dysfunction by β-Caryophyllene: A Focus on the Nervous System. Antioxidants (Basel) 2021; 10:546. [PMID: 33915950 PMCID: PMC8066981 DOI: 10.3390/antiox10040546] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/19/2021] [Accepted: 03/28/2021] [Indexed: 02/05/2023] Open
Abstract
Mitochondrial dysfunction results in a series of defective cellular events, including decreased adenosine triphosphate (ATP) production, enhanced reactive oxygen species (ROS) output, and altered proteastasis and cellular quality control. An enhanced output of ROS may damage mitochondrial components, such as mitochondrial DNA and elements of the electron transport chain, resulting in the loss of proper electrochemical gradient across the mitochondrial inner membrane and an ensuing shutdown of mitochondrial energy production. Neurons have an increased demand for ATP and oxygen, and thus are more prone to damage induced by mitochondrial dysfunction. Mitochondrial dysfunction, damaged electron transport chains, altered membrane permeability and Ca2+ homeostasis, and impaired mitochondrial defense systems induced by oxidative stress, are pathological changes involved in neurodegenerative disorders. A growing body of evidence suggests that the use of antioxidants could stabilize mitochondria and thus may be suitable for preventing neuronal loss. Numerous natural products exhibit the potential to counter oxidative stress and mitochondrial dysfunction; however, science is still looking for a breakthrough in the treatment of neurodegenerative disorders. β-caryophyllene is a bicyclic sesquiterpene, and an active principle of essential oils derived from a large number of spices and food plants. As a selective cannabinoid receptor 2 (CB2) agonist, several studies have reported it as possessing numerous pharmacological activities such as antibacterial (e.g., Helicobacter pylori), antioxidant, anti-inflammatory, analgesic (e.g., neuropathic pain), anti-neurodegenerative and anticancer properties. The present review mainly focuses on the potential of β-caryophyllene in reducing oxidative stress and mitochondrial dysfunction, and its possible links with neuroprotection.
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Affiliation(s)
- Hammad Ullah
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; (H.U.); (A.D.M.); (C.S.)
| | - Alessandro Di Minno
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; (H.U.); (A.D.M.); (C.S.)
- CEINGE-Biotecnologie Avanzate, 80131 Naples, Italy
| | - Cristina Santarcangelo
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; (H.U.); (A.D.M.); (C.S.)
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan; or
| | - Maria Daglia
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; (H.U.); (A.D.M.); (C.S.)
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
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25
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Cyrino LAR, Delwing-de Lima D, Ullmann OM, Maia TP. Concepts of Neuroinflammation and Their Relationship With Impaired Mitochondrial Functions in Bipolar Disorder. Front Behav Neurosci 2021; 15:609487. [PMID: 33732117 PMCID: PMC7959852 DOI: 10.3389/fnbeh.2021.609487] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/18/2021] [Indexed: 12/24/2022] Open
Abstract
Bipolar disorder (BD) is a chronic psychiatric disease, characterized by frequent behavioral episodes of depression and mania, and neurologically by dysregulated neurotransmission, neuroplasticity, growth factor signaling, and metabolism, as well as oxidative stress, and neuronal apoptosis, contributing to chronic neuroinflammation. These abnormalities result from complex interactions between multiple susceptibility genes and environmental factors such as stress. The neurocellular abnormalities of BD can result in gross morphological changes, such as reduced prefrontal and hippocampal volume, and circuit reorganization resulting in cognitive and emotional deficits. The term "neuroprogression" is used to denote the progressive changes from early to late stages, as BD severity and loss of treatment response correlate with the number of past episodes. In addition to circuit and cellular abnormalities, BD is associated with dysfunctional mitochondria, leading to severe metabolic disruption in high energy-demanding neurons and glia. Indeed, mitochondrial dysfunction involving electron transport chain (ETC) disruption is considered the primary cause of chronic oxidative stress in BD. The ensuing damage to membrane lipids, proteins, and DNA further perpetuates oxidative stress and neuroinflammation, creating a perpetuating pathogenic cycle. A deeper understanding of BD pathophysiology and identification of associated biomarkers of neuroinflammation are needed to facilitate early diagnosis and treatment of this debilitating disorder.
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Affiliation(s)
- Luiz Arthur Rangel Cyrino
- Programa de Pós-Graduação em Saúde e Meio Ambiente, Laboratório de Práticas Farmacêuticas of Department of Pharmacy, University of Joinville Region—UNIVILLE, Joinville, Brazil
- Department of Psychology, University of Joinville—UNIVILLE, Joinville, Brazil
- Department of Pharmacy, University of Joinville—UNIVILLE, Joinville, Brazil
| | - Daniela Delwing-de Lima
- Programa de Pós-Graduação em Saúde e Meio Ambiente, Laboratório de Práticas Farmacêuticas of Department of Pharmacy, University of Joinville Region—UNIVILLE, Joinville, Brazil
- Department of Pharmacy, University of Joinville—UNIVILLE, Joinville, Brazil
- Department of Medicine, University of Joinville—UNIVILLE, Joinville, Brazil
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26
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Giachin G, Jessop M, Bouverot R, Acajjaoui S, Saïdi M, Chretien A, Bacia‐Verloop M, Signor L, Mas PJ, Favier A, Borel Meneroud E, Hons M, Hart DJ, Kandiah E, Boeri Erba E, Buisson A, Leonard G, Gutsche I, Soler‐Lopez M. Assembly of The Mitochondrial Complex I Assembly Complex Suggests a Regulatory Role for Deflavination. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202011548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Gabriele Giachin
- Structural Biology Group European Synchrotron Radiation Facility (ESRF) 71 avenue des Martyrs 38043 Grenoble France
| | - Matthew Jessop
- Institut de Biologie Structurale (IBS) CNRS, CEA Université Grenoble Alpes 71 avenue des Martyrs 38044 Grenoble France
| | - Romain Bouverot
- Structural Biology Group European Synchrotron Radiation Facility (ESRF) 71 avenue des Martyrs 38043 Grenoble France
| | - Samira Acajjaoui
- Structural Biology Group European Synchrotron Radiation Facility (ESRF) 71 avenue des Martyrs 38043 Grenoble France
| | - Melissa Saïdi
- Structural Biology Group European Synchrotron Radiation Facility (ESRF) 71 avenue des Martyrs 38043 Grenoble France
| | - Anaïs Chretien
- Structural Biology Group European Synchrotron Radiation Facility (ESRF) 71 avenue des Martyrs 38043 Grenoble France
| | - Maria Bacia‐Verloop
- Institut de Biologie Structurale (IBS) CNRS, CEA Université Grenoble Alpes 71 avenue des Martyrs 38044 Grenoble France
| | - Luca Signor
- Institut de Biologie Structurale (IBS) CNRS, CEA Université Grenoble Alpes 71 avenue des Martyrs 38044 Grenoble France
| | - Philippe J. Mas
- Integrated Structural Biology Grenoble (ISBG) CNRS CEA, Université Grenoble Alpes 71 avenue des Martyrs 38042 Grenoble France
| | - Adrien Favier
- Institut de Biologie Structurale (IBS) CNRS, CEA Université Grenoble Alpes 71 avenue des Martyrs 38044 Grenoble France
| | - Eve Borel Meneroud
- Grenoble Institut des Neurosciences (GIN) Centre Inserm U1216 Equipe Neuropathologies et Dysfonctions Synaptiques Université Grenoble Alpes 31 Chemin Fortuné Ferrini 38700 La Tronche France
| | - Michael Hons
- European Molecular Biology Laboratory (EMBL) Grenoble Outstation 71 avenue des Martyrs 38042 Grenoble France
| | - Darren J. Hart
- Institut de Biologie Structurale (IBS) CNRS, CEA Université Grenoble Alpes 71 avenue des Martyrs 38044 Grenoble France
| | - Eaazhisai Kandiah
- Structural Biology Group European Synchrotron Radiation Facility (ESRF) 71 avenue des Martyrs 38043 Grenoble France
| | - Elisabetta Boeri Erba
- Institut de Biologie Structurale (IBS) CNRS, CEA Université Grenoble Alpes 71 avenue des Martyrs 38044 Grenoble France
| | - Alain Buisson
- Grenoble Institut des Neurosciences (GIN) Centre Inserm U1216 Equipe Neuropathologies et Dysfonctions Synaptiques Université Grenoble Alpes 31 Chemin Fortuné Ferrini 38700 La Tronche France
| | - Gordon Leonard
- Structural Biology Group European Synchrotron Radiation Facility (ESRF) 71 avenue des Martyrs 38043 Grenoble France
| | - Irina Gutsche
- Institut de Biologie Structurale (IBS) CNRS, CEA Université Grenoble Alpes 71 avenue des Martyrs 38044 Grenoble France
| | - Montserrat Soler‐Lopez
- Structural Biology Group European Synchrotron Radiation Facility (ESRF) 71 avenue des Martyrs 38043 Grenoble France
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27
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Giachin G, Jessop M, Bouverot R, Acajjaoui S, Saïdi M, Chretien A, Bacia-Verloop M, Signor L, Mas PJ, Favier A, Borel Meneroud E, Hons M, Hart DJ, Kandiah E, Boeri Erba E, Buisson A, Leonard G, Gutsche I, Soler-Lopez M. Assembly of The Mitochondrial Complex I Assembly Complex Suggests a Regulatory Role for Deflavination. Angew Chem Int Ed Engl 2021; 60:4689-4697. [PMID: 33320993 PMCID: PMC7986633 DOI: 10.1002/anie.202011548] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Indexed: 01/01/2023]
Abstract
Fatty acid β‐oxidation (FAO) and oxidative phosphorylation (OXPHOS) are mitochondrial redox processes that generate ATP. The biogenesis of the respiratory Complex I, a 1 MDa multiprotein complex that is responsible for initiating OXPHOS, is mediated by assembly factors including the mitochondrial complex I assembly (MCIA) complex. However, the organisation and the role of the MCIA complex are still unclear. Here we show that ECSIT functions as the bridging node of the MCIA core complex. Furthermore, cryo‐electron microscopy together with biochemical and biophysical experiments reveal that the C‐terminal domain of ECSIT directly binds to the vestigial dehydrogenase domain of the FAO enzyme ACAD9 and induces its deflavination, switching ACAD9 from its role in FAO to an MCIA factor. These findings provide the structural basis for the MCIA complex architecture and suggest a unique molecular mechanism for coordinating the regulation of the FAO and OXPHOS pathways to ensure an efficient energy production.
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Affiliation(s)
- Gabriele Giachin
- Structural Biology Group, European Synchrotron Radiation Facility (ESRF), 71 avenue des Martyrs, 38043, Grenoble, France
| | - Matthew Jessop
- Institut de Biologie Structurale (IBS), CNRS, CEA, Université Grenoble Alpes, 71 avenue des Martyrs, 38044, Grenoble, France
| | - Romain Bouverot
- Structural Biology Group, European Synchrotron Radiation Facility (ESRF), 71 avenue des Martyrs, 38043, Grenoble, France
| | - Samira Acajjaoui
- Structural Biology Group, European Synchrotron Radiation Facility (ESRF), 71 avenue des Martyrs, 38043, Grenoble, France
| | - Melissa Saïdi
- Structural Biology Group, European Synchrotron Radiation Facility (ESRF), 71 avenue des Martyrs, 38043, Grenoble, France
| | - Anaïs Chretien
- Structural Biology Group, European Synchrotron Radiation Facility (ESRF), 71 avenue des Martyrs, 38043, Grenoble, France
| | - Maria Bacia-Verloop
- Institut de Biologie Structurale (IBS), CNRS, CEA, Université Grenoble Alpes, 71 avenue des Martyrs, 38044, Grenoble, France
| | - Luca Signor
- Institut de Biologie Structurale (IBS), CNRS, CEA, Université Grenoble Alpes, 71 avenue des Martyrs, 38044, Grenoble, France
| | - Philippe J Mas
- Integrated Structural Biology Grenoble (ISBG) CNRS, CEA, Université Grenoble Alpes, 71 avenue des Martyrs, 38042, Grenoble, France
| | - Adrien Favier
- Institut de Biologie Structurale (IBS), CNRS, CEA, Université Grenoble Alpes, 71 avenue des Martyrs, 38044, Grenoble, France
| | - Eve Borel Meneroud
- Grenoble Institut des Neurosciences (GIN), Centre Inserm U1216, Equipe Neuropathologies et Dysfonctions Synaptiques, Université Grenoble Alpes, 31 Chemin Fortuné Ferrini, 38700, La Tronche, France
| | - Michael Hons
- European Molecular Biology Laboratory (EMBL), Grenoble Outstation, 71 avenue des Martyrs, 38042, Grenoble, France
| | - Darren J Hart
- Institut de Biologie Structurale (IBS), CNRS, CEA, Université Grenoble Alpes, 71 avenue des Martyrs, 38044, Grenoble, France
| | - Eaazhisai Kandiah
- Structural Biology Group, European Synchrotron Radiation Facility (ESRF), 71 avenue des Martyrs, 38043, Grenoble, France
| | - Elisabetta Boeri Erba
- Institut de Biologie Structurale (IBS), CNRS, CEA, Université Grenoble Alpes, 71 avenue des Martyrs, 38044, Grenoble, France
| | - Alain Buisson
- Grenoble Institut des Neurosciences (GIN), Centre Inserm U1216, Equipe Neuropathologies et Dysfonctions Synaptiques, Université Grenoble Alpes, 31 Chemin Fortuné Ferrini, 38700, La Tronche, France
| | - Gordon Leonard
- Structural Biology Group, European Synchrotron Radiation Facility (ESRF), 71 avenue des Martyrs, 38043, Grenoble, France
| | - Irina Gutsche
- Institut de Biologie Structurale (IBS), CNRS, CEA, Université Grenoble Alpes, 71 avenue des Martyrs, 38044, Grenoble, France
| | - Montserrat Soler-Lopez
- Structural Biology Group, European Synchrotron Radiation Facility (ESRF), 71 avenue des Martyrs, 38043, Grenoble, France
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28
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Kušíková K, Feichtinger RG, Csillag B, Kalev OK, Weis S, Duba HC, Mayr JA, Weis D. Case Report and Review of the Literature: A New and a Recurrent Variant in the VARS2 Gene Are Associated With Isolated Lethal Hypertrophic Cardiomyopathy, Hyperlactatemia, and Pulmonary Hypertension in Early Infancy. Front Pediatr 2021; 9:660076. [PMID: 33937156 PMCID: PMC8085550 DOI: 10.3389/fped.2021.660076] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 03/22/2021] [Indexed: 01/01/2023] Open
Abstract
Mitochondriopathies represent a wide spectrum of miscellaneous disorders with multisystem involvement, which are caused by various genetic changes. The establishment of the diagnosis of mitochondriopathy is often challenging. Recently, several mutations of the VARS2 gene encoding the mitochondrial valyl-tRNA synthetase were associated with early onset encephalomyopathies or encephalocardiomyopathies with major clinical features such as hypotonia, developmental delay, brain MRI changes, epilepsy, hypertrophic cardiomyopathy, and plasma lactate elevation. However, the correlation between genotype and phenotype still remains unclear. In this paper we present a male Caucasian patient with a recurrent c.1168G>A (p.Ala390Thr) and a new missense biallelic variant c.2758T>C (p.Tyr920His) in the VARS2 gene which were detected by whole exome sequencing (WES). VARS2 protein was reduced in the patient's muscle. A resulting defect of oxidative phosphorylation (OXPHOS) was proven by enzymatic assay, western blotting and immunohistochemistry from a homogenate of skeletal muscle tissue. Clinical signs of our patient included hyperlactatemia, hypertrophic cardiomyopathy (HCM) and pulmonary hypertension, which led to early death at the age of 47 days without any other known accompanying signs. The finding of novel variants in the VARS2 gene expands the spectrum of known mutations and phenotype presentation. Based on our findings we recommend to consider possible mitochondriopathy and to include the analysis of the VARS2 gene in the genetic diagnostic algorithm in cases with early manifesting and rapidly progressing HCM with hyperlactatemia.
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Affiliation(s)
- Katarína Kušíková
- Department of Pediatric Neurology, Medical School, Comenius University and National Institute of Children's Diseases, Bratislava, Slovakia
| | - René Günther Feichtinger
- Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Bernhard Csillag
- Department of Neonatology, Kepler University Hospital Med Campus IV, Johannes Kepler University Linz, Linz, Austria
| | - Ognian Kostadinov Kalev
- Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University Hospital Neuromed Campus, Johannes Kepler University Linz, Linz, Austria
| | - Serge Weis
- Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University Hospital Neuromed Campus, Johannes Kepler University Linz, Linz, Austria
| | - Hans-Christoph Duba
- Department of Medical Genetics, Kepler University Hospital Med Campus IV, Johannes Kepler University Linz, Linz, Austria
| | - Johannes Adalbert Mayr
- Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Denisa Weis
- Department of Medical Genetics, Kepler University Hospital Med Campus IV, Johannes Kepler University Linz, Linz, Austria
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Oxidative Stress-Mediated Blood-Brain Barrier (BBB) Disruption in Neurological Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020. [DOI: 10.1155/2020/4356386] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The blood-brain barrier (BBB), as a crucial gate of brain-blood molecular exchange, is involved in the pathogenesis of multiple neurological diseases. Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) and the scavenger system. Since oxidative stress plays a significant role in the production and maintenance of the BBB, the cerebrovascular system is especially vulnerable to it. The pathways that initiate BBB dysfunction include, but are not limited to, mitochondrial dysfunction, excitotoxicity, iron metabolism, cytokines, pyroptosis, and necroptosis, all converging on the generation of ROS. Interestingly, ROS also provide common triggers that directly regulate BBB damage, parameters including tight junction (TJ) modifications, transporters, matrix metalloproteinase (MMP) activation, inflammatory responses, and autophagy. We will discuss the role of oxidative stress-mediated BBB disruption in neurological diseases, such as hemorrhagic stroke, ischemic stroke (IS), Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and cerebral small vessel disease (CSVD). This review will also discuss the latest clinical evidence of potential biomarkers and antioxidant drugs towards oxidative stress in neurological diseases. A deeper understanding of how oxidative stress damages BBB may open up more therapeutic options for the treatment of neurological diseases.
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Neganova ME, Aleksandrova YR, Nebogatikov VO, Klochkov SG, Ustyugov AA. Promising Molecular Targets for Pharmacological Therapy of Neurodegenerative Pathologies. Acta Naturae 2020; 12:60-80. [PMID: 33173597 PMCID: PMC7604899 DOI: 10.32607/actanaturae.10925] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 04/20/2020] [Indexed: 12/12/2022] Open
Abstract
Drug development for the treatment of neurodegenerative diseases has to confront numerous problems occurring, in particular, because of attempts to address only one of the causes of the pathogenesis of neurological disorders. Recent advances in multitarget therapy research are gaining momentum by utilizing pharmacophores that simultaneously affect different pathological pathways in the neurodegeneration process. The application of such a therapeutic strategy not only involves the treatment of symptoms, but also mainly addresses prevention of the fundamental pathological processes of neurodegenerative diseases and the reduction of cognitive abilities. Neuroinflammation and oxidative stress, mitochondrial dysfunction, dysregulation of the expression of histone deacetylases, and aggregation of pathogenic forms of proteins are among the most common and significant pathological features of neurodegenerative diseases. In this review, we focus on the molecular mechanisms and highlight the main aspects, including reactive oxygen species, the cell endogenous antioxidant system, neuroinflammation triggers, metalloproteinases, α-synuclein, tau proteins, neuromelanin, histone deacetylases, presenilins, etc. The processes and molecular targets discussed in this review could serve as a starting point for screening leader compounds that could help prevent or slow down the development of neurodegenerative diseases.
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Affiliation(s)
- M. E. Neganova
- Institute of Physiologically Active Compounds of the Russian Academy of Sciences, Moscow region, Chernogolovka, 142432 Russia
| | - Yu. R. Aleksandrova
- Institute of Physiologically Active Compounds of the Russian Academy of Sciences, Moscow region, Chernogolovka, 142432 Russia
| | - V. O. Nebogatikov
- Institute of Physiologically Active Compounds of the Russian Academy of Sciences, Moscow region, Chernogolovka, 142432 Russia
| | - S. G. Klochkov
- Institute of Physiologically Active Compounds of the Russian Academy of Sciences, Moscow region, Chernogolovka, 142432 Russia
| | - A. A. Ustyugov
- Institute of Physiologically Active Compounds of the Russian Academy of Sciences, Moscow region, Chernogolovka, 142432 Russia
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Bie AS, Cömert C, Körner R, Corydon TJ, Palmfeldt J, Hipp MS, Hartl FU, Bross P. An inventory of interactors of the human HSP60/HSP10 chaperonin in the mitochondrial matrix space. Cell Stress Chaperones 2020; 25:407-416. [PMID: 32060690 PMCID: PMC7192978 DOI: 10.1007/s12192-020-01080-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/14/2020] [Accepted: 02/10/2020] [Indexed: 10/25/2022] Open
Abstract
The HSP60/HSP10 chaperonin assists folding of proteins in the mitochondrial matrix space by enclosing them in its central cavity. The chaperonin forms part of the mitochondrial protein quality control system. It is essential for cellular survival and mutations in its subunits are associated with rare neurological disorders. Here we present the first survey of interactors of the human mitochondrial HSP60/HSP10 chaperonin. Using a protocol involving metabolic labeling of HEK293 cells, cross-linking, and immunoprecipitation of HSP60, we identified 323 interacting proteins. As expected, the vast majority of these proteins are localized to the mitochondrial matrix space. We find that approximately half of the proteins annotated as mitochondrial matrix proteins interact with the HSP60/HSP10 chaperonin. They cover a broad spectrum of functions and metabolic pathways including the mitochondrial protein synthesis apparatus, the respiratory chain, and mitochondrial protein quality control. Many of the genes encoding HSP60 interactors are annotated as disease genes. There is a correlation between relative cellular abundance and relative abundance in the HSP60 immunoprecipitates. Nineteen abundant matrix proteins occupy more than 60% of the HSP60/HSP10 chaperonin capacity. The reported inventory of interactors can form the basis for interrogating which proteins are especially dependent on the chaperonin.
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Affiliation(s)
- Anne Sigaard Bie
- Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
| | - Cagla Cömert
- Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
| | - Roman Körner
- Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152, Martinsried, Germany
| | - Thomas J Corydon
- Department of Biomedicine, Aarhus University, Hoegh-Guldbergsgade 10, 8000, Aarhus C, Denmark
- Department of Ophthalmology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
| | - Johan Palmfeldt
- Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
| | - Mark S Hipp
- Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152, Martinsried, Germany
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands
- School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26111, Oldenburg, Germany
| | - F Ulrich Hartl
- Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152, Martinsried, Germany
| | - Peter Bross
- Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark.
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Mukherjee S, Ghosh A. Molecular mechanism of mitochondrial respiratory chain assembly and its relation to mitochondrial diseases. Mitochondrion 2020; 53:1-20. [PMID: 32304865 DOI: 10.1016/j.mito.2020.04.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 03/28/2020] [Accepted: 04/07/2020] [Indexed: 12/17/2022]
Abstract
The mitochondrial respiratory chain (MRC) is comprised of ~92 nuclear and mitochondrial DNA-encoded protein subunits that are organized into five different multi-subunit respiratory complexes. These complexes produce 90% of the ATP required for cell sustenance. Specific sets of subunits are assembled in a modular or non-modular fashion to construct the MRC complexes. The complete assembly process is gradually chaperoned by a myriad of assembly factors that must coordinate with several other prosthetic groups to reach maturity, makingthe entire processextensively complicated. Further, the individual respiratory complexes can be integrated intovarious giant super-complexes whose functional roles have yet to be explored. Mutations in the MRC subunits and in the related assembly factors often give rise to defects in the proper assembly of the respiratory chain, which then manifests as a group of disorders called mitochondrial diseases, the most common inborn errors of metabolism. This review summarizes the current understanding of the biogenesis of individual MRC complexes and super-complexes, and explores how mutations in the different subunits and assembly factors contribute to mitochondrial disease pathology.
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Affiliation(s)
- Soumyajit Mukherjee
- Department of Biochemistry, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700019, India
| | - Alok Ghosh
- Department of Biochemistry, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700019, India.
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Bagwe-Parab S, Kaur G. Molecular targets and therapeutic interventions for iron induced neurodegeneration. Brain Res Bull 2020; 156:1-9. [DOI: 10.1016/j.brainresbull.2019.12.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 12/14/2019] [Accepted: 12/17/2019] [Indexed: 01/17/2023]
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Agnihotri A, Aruoma OI. Alzheimer’s Disease and Parkinson’s Disease: A Nutritional Toxicology Perspective of the Impact of Oxidative Stress, Mitochondrial Dysfunction, Nutrigenomics and Environmental Chemicals. J Am Coll Nutr 2019; 39:16-27. [DOI: 10.1080/07315724.2019.1683379] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
| | - Okezie I. Aruoma
- Department of Chemistry and Biochemistry, College of Natural and Social Sciences, California State University Los Angeles, Los Angeles, California, USA
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Ruzman L, Kolic I, Radic Nisevic J, Ruzic Barsic A, Skarpa Prpic I, Prpic I. A novel VARS2 gene variant in a patient with epileptic encephalopathy. Ups J Med Sci 2019; 124:273-277. [PMID: 31623496 PMCID: PMC6968568 DOI: 10.1080/03009734.2019.1670297] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background: Mitochondrial disorders are heterogeneous clinical syndromes caused by defective activity in the mitochondrial respiratory chain, resulting in a faulty oxidative phosphorylation system. These inherited disorders are individually rare, and furthermore they are phenotypic variables. The genetically characterized mitochondrial disorders are rarely associated with epileptic encephalopathies.Case presentation: We present the clinical phenotype, biochemical analysis, and electrographic and neuro-radiological features of a 5-month-old girl with epileptic encephalopathy, microcephaly, severe psychomotor delay, hypertrophic cardiomyopathy, and abnormal MRI scan. Using whole-genome sequencing technique, compound heterozygous mutations of the VARS2 gene were revealed, with one previously unreported frameshift mutation.Conclusion: Our report extends the phenotypic spectrum of VARS2-related disorders with an initial presentation of epileptic encephalopathy and early death due to malignant arrhythmia.
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Affiliation(s)
- Lucija Ruzman
- Child Neurology and Child Psychiatry Department, Pediatric Clinic, Clinical Hospital Center Rijeka, Rijeka, Croatia
| | - Ivana Kolic
- Child Neurology and Child Psychiatry Department, Pediatric Clinic, Clinical Hospital Center Rijeka, Rijeka, Croatia
| | - Jelena Radic Nisevic
- Child Neurology and Child Psychiatry Department, Pediatric Clinic, Clinical Hospital Center Rijeka, Rijeka, Croatia
- University of Rijeka, School of Medicine Rijeka, Rijeka, Croatia
| | | | | | - Igor Prpic
- Child Neurology and Child Psychiatry Department, Pediatric Clinic, Clinical Hospital Center Rijeka, Rijeka, Croatia
- University of Rijeka, School of Medicine Rijeka, Rijeka, Croatia
- CONTACT Igor Prpic Child Neurology and Child Psychiatry Department, Pediatric Clinic, Clinical Hospital Center Rijeka, Istarska 43, 51000 Rijeka, Croatia
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Pillai AB, Muthuraman KR, Mariappan V, Belur SS, Lokesh S, Rajendiran S. Oxidative stress response in the pathogenesis of dengue virus virulence, disease prognosis and therapeutics: an update. Arch Virol 2019; 164:2895-2908. [PMID: 31531742 DOI: 10.1007/s00705-019-04406-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 08/09/2019] [Indexed: 12/26/2022]
Abstract
Dengue virus (DENV) is a mosquito-borne arbovirus that causes febrile illness and can lead to a potentially lethal disease. The mechanism of disease pathogenesis is not completely understood, and there are currently no vaccines or therapeutic drugs available to protect against all four serotypes of DENV. Although many reasons have been suggested for the development of the disease, dengue studies have shown that, during DENV infection, there is an imbalance between oxidants and antioxidants that disrupts homeostasis. An increase in reactive oxygen species (ROS) levels triggers the sudden release of cytokines, which can lead to plasma leakage and other severe symptoms. In the present review, we give an overview of the oxidative stress response and its effect on the progression of dengue disease. We also discuss the role of oxidative-stress-associated molecules in disease prognostic and therapeutics.
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Affiliation(s)
- Agieshkumar Balakrishna Pillai
- Central Inter-Disciplinary Research Facility (CIDRF), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607 402, India.
| | | | - Vignesh Mariappan
- Central Inter-Disciplinary Research Facility (CIDRF), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607 402, India
| | | | - S Lokesh
- Department of General Medicine, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607 402, India
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Targeted next generation sequencing identifies novel pathogenic variants and provides molecular diagnoses in a cohort of pediatric and adult patients with unexplained mitochondrial dysfunction. Mitochondrion 2019; 47:309-317. [DOI: 10.1016/j.mito.2019.02.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 01/14/2019] [Accepted: 02/26/2019] [Indexed: 12/28/2022]
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Polyzos AA, Lee DY, Datta R, Hauser M, Budworth H, Holt A, Mihalik S, Goldschmidt P, Frankel K, Trego K, Bennett MJ, Vockley J, Xu K, Gratton E, McMurray CT. Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice. Cell Metab 2019; 29:1258-1273.e11. [PMID: 30930170 PMCID: PMC6583797 DOI: 10.1016/j.cmet.2019.03.004] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 10/25/2018] [Accepted: 03/05/2019] [Indexed: 12/23/2022]
Abstract
The basis for region-specific neuronal toxicity in Huntington disease is unknown. Here, we show that region-specific neuronal vulnerability is a substrate-driven response in astrocytes. Glucose is low in HdhQ(150/150) animals, and astrocytes in each brain region adapt by metabolically reprogramming their mitochondria to use endogenous, non-glycolytic metabolites as an alternative fuel. Each region is characterized by distinct metabolic pools, and astrocytes adapt accordingly. The vulnerable striatum is enriched in fatty acids, and mitochondria reprogram by oxidizing them as an energy source but at the cost of escalating reactive oxygen species (ROS)-induced damage. The cerebellum is replete with amino acids, which are precursors for glucose regeneration through the pentose phosphate shunt or gluconeogenesis pathways. ROS is not elevated, and this region sustains little damage. While mhtt expression imposes disease stress throughout the brain, sensitivity or resistance arises from an adaptive stress response, which is inherently region specific. Metabolic reprogramming may have relevance to other diseases.
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Affiliation(s)
- Aris A Polyzos
- Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Do Yup Lee
- Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Rupsa Datta
- Laboratory for Fluorescence Dynamics, Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA
| | - Meghan Hauser
- Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Helen Budworth
- Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Amy Holt
- Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Stephanie Mihalik
- Department of Pediatrics at Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
| | - Pike Goldschmidt
- Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Ken Frankel
- Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Kelly Trego
- Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Michael J Bennett
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Jerry Vockley
- Department of Pediatrics at Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
| | - Ke Xu
- Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Enrico Gratton
- Laboratory for Fluorescence Dynamics, Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA
| | - Cynthia T McMurray
- Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
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Salidroside Protects Dopaminergic Neurons by Preserving Complex I Activity via DJ-1/Nrf2-Mediated Antioxidant Pathway. PARKINSONS DISEASE 2019; 2019:6073496. [PMID: 31223467 PMCID: PMC6541949 DOI: 10.1155/2019/6073496] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 03/09/2019] [Accepted: 04/01/2019] [Indexed: 01/08/2023]
Abstract
The pathogenic mechanism of Parkinson's disease (PD) remains to be elucidated; however, mitochondrial dysfunction at the level of complex I and oxidative stress is suggestively involved in the development of PD. In our previous work, salidroside (Sal), an active component extracted from the medicinal plant Rhodiola rosea L., might protect dopaminergic (DA) neurons through modulating ROS–NO-related pathway. However, the mechanism of Sal-induced neuroprotective effects against PD remains poorly understood. Therefore, we further investigated whether Sal plays neuroprotective effects by activating complex I via DJ-1/Nrf2-mediated antioxidant pathway. The results showed that Sal remarkably attenuated MPP+/MPTP-induced decline in cell viability, accompanied by decreases in reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxy-deoxyguanosine (8-OHdG) contents and increases in the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), as well as glutathione (GSH) levels. Furthermore, Sal greatly improved the behavioral performance and prevented the severe reduction of TH-positive neuron numbers in the substantia nigra (SN). Moreover, in comparison with the MPP+/MPTP group, Sal increased the nuclear translocation of DJ-1 and Nrf2 and the mitochondrial translocation of DJ-1, accompanied by activating complex I. Furthermore, silencing of DJ-1/Nrf2 inhibited the increase of complex I activity and cell viability elicited by Sal. Together, these results support the neuroprotective effect of Sal against MPP+/MPTP-induced DA neurons damage.
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Zhu MY, Zhang DL, Zhou C, Chai Z. Mild Acidosis Protects Neurons during Oxygen-Glucose Deprivation by Reducing Loss of Mitochondrial Respiration. ACS Chem Neurosci 2019; 10:2489-2497. [PMID: 30835994 DOI: 10.1021/acschemneuro.8b00737] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Brain ischemia is often accompanied by brain acidosis and this acidosis can affect ischemic neuronal injury. Ischemic neuronal injury is initiated by a decrease in ATP production which mainly relies on mitochondrial oxidative phosphorylation. Ischemia often causes mitochondrial dysfunction, and acidosis has been found to affect mitochondrial function, suggesting that acidosis accompanying ischemia may influence neurons by targeting mitochondrial metabolism. However, the effects of acidosis on mitochondrial energy metabolism during ischemia lacks thorough investigation. Here, we found that mild acidosis significantly reduced neuronal death possibly by slowing the process of ATP deprivation during oxygen-glucose deprivation (OGD), an in vitro ischemic model. The maintaining of neuronal ATP depended on protecting mitochondrial ATP production. Further investigation of mitochondrial function revealed that mild acidosis alleviated OGD-induced collapse of mitochondrial membrane potentials as well as damage to respiratory function, at least in part by reducing impacts on complex I and II activities. Inhibition of complex I activity aggravated neuronal death, which suggests that the contribution of mild acidosis to maintaining complex I activity promoted neuronal survival during OGD. Our findings reveal maintaining mitochondrial respiration as a new possible protective mechanism of mild acidosis during ischemia, on neurons.
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Affiliation(s)
- Ming-Yue Zhu
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China
| | - Dong-Liang Zhang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China
| | - Chen Zhou
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China
| | - Zhen Chai
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China
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ACP Acylation Is an Acetyl-CoA-Dependent Modification Required for Electron Transport Chain Assembly. Mol Cell 2019; 71:567-580.e4. [PMID: 30118679 DOI: 10.1016/j.molcel.2018.06.039] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 06/08/2018] [Accepted: 06/25/2018] [Indexed: 01/28/2023]
Abstract
The electron transport chain (ETC) is an important participant in cellular energy conversion, but its biogenesis presents the cell with numerous challenges. To address these complexities, the cell utilizes ETC assembly factors, which include the LYR protein family. Each member of this family interacts with the mitochondrial acyl carrier protein (ACP), the scaffold protein upon which the mitochondrial fatty acid synthesis (mtFAS) pathway builds fatty acyl chains from acetyl-CoA. We demonstrate that the acylated form of ACP is an acetyl-CoA-dependent allosteric activator of the LYR protein family used to stimulate ETC biogenesis. By tuning ETC assembly to the abundance of acetyl-CoA, which is the major fuel of the TCA cycle and ETC, this system could provide an elegant mechanism for coordinating the assembly of ETC complexes with one another and with substrate availability.
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Bajpai P, Koc E, Sonpavde G, Singh R, Singh KK. Mitochondrial localization, import, and mitochondrial function of the androgen receptor. J Biol Chem 2019; 294:6621-6634. [PMID: 30792308 DOI: 10.1074/jbc.ra118.006727] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 12/14/2018] [Indexed: 12/23/2022] Open
Abstract
Nuclear localization of androgen receptor (AR) directs transcriptional regulation of a host of genes, referred to as genomic signaling. Additionally, nonnuclear or nongenomic activities of the AR have long been described, but understanding of these activities remains elusive. Here, we report that AR is imported into and localizes to mitochondria and has a novel role in regulating multiple mitochondrial processes. Employing complementary experimental approaches of AR knockdown in AR-expressing cells and ectopic AR expression in AR-deficient cells, we demonstrate an inverse relationship between AR expression and mitochondrial DNA (mtDNA) content and transcription factor A, mitochondrial (TFAM), a regulator of mtDNA content. We show that AR localizes to mitochondria in prostate tissues and cell lines and is imported into mitochondria in vitro We also found that AR contains a 36-amino-acid-long mitochondrial localization sequence (MLS) capable of targeting a passenger protein (GFP) to the mitochondria and that deletion of the MLS abolishes the import of AR into the mitochondria. Ectopic AR expression reduced the expression of oxidative phosphorylation (OXPHOS) subunits. Interestingly, AR also controlled translation of mtDNA-encoded genes by regulating expression of multiple nuclear DNA-encoded mitochondrial ribosomal proteins. Consistent with these observations, OXPHOS supercomplexes were destabilized, and OXPHOS enzymatic activities were reduced in AR-expressing cells and restored upon AR knockdown. Moreover, mitochondrial impairment induced AR expression and increased its translocation into mitochondria. We conclude that AR localizes to mitochondria, where it controls multiple mitochondrial functions and mitonuclear communication. Our studies also suggest that mitochondria are novel players in nongenomic activities of AR.
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Affiliation(s)
| | - Emine Koc
- the Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia 25701
| | - Guru Sonpavde
- the Dana Farber Cancer Institute, Boston, Massachusetts 02215, and
| | | | - Keshav K Singh
- From the Department of Genetics, .,Departments of Pathology and Environmental Health.,Center for Free Radical Biology.,Center for Aging, and.,UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294.,the Veterans Affairs Medical Center, Birmingham, Alabama 35294
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Urea cycle dysregulation in non-alcoholic fatty liver disease. J Hepatol 2018; 69:905-915. [PMID: 29981428 DOI: 10.1016/j.jhep.2018.06.023] [Citation(s) in RCA: 131] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 06/22/2018] [Accepted: 06/24/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS In non-alcoholic steatohepatitis (NASH), the function of urea cycle enzymes (UCEs) may be affected, resulting in hyperammonemia and the risk of disease progression. We aimed to determine whether the expression and function of UCEs are altered in an animal model of NASH and in patients with non-alcoholic fatty liver disease (NAFLD), and whether this process is reversible. METHODS Rats were first fed a high-fat, high-cholesterol diet for 10 months to induce NASH, before being switched onto a normal chow diet to recover. In humans, we obtained liver biopsies from 20 patients with steatosis and 15 with NASH. Primary rat hepatocytes were isolated and cultured with free fatty acids. We measured the gene and protein expression of ornithine transcarbamylase (OTC) and carbamoylphosphate synthetase (CPS1), as well as OTC activity, and ammonia concentrations. Moreover, we assessed the promoter methylation status of OTC and CPS1 in rats, humans and steatotic hepatocytes. RESULTS In NASH animals, gene and protein expression of OTC and CPS1, and the activity of OTC, were reversibly reduced. Hypermethylation of Otc promoter genes was also observed. Additionally, in patients with NAFLD, OTC enzyme concentration and activity were reduced and ammonia concentrations were increased, which was further exacerbated in those with NASH. Furthermore, OTC and CPS1 promoter regions were hypermethylated. In primary hepatocytes, induction of steatosis was associated with Otc promoter hypermethylation, a reduction in the gene expression of Otc and Cps1, and an increase in ammonia concentration in the supernatant. CONCLUSION NASH is associated with a reduction in the gene and protein expression, and activity, of UCEs. This results in hyperammonemia, possibly through hypermethylation of UCE genes and impairment of urea synthesis. Our investigations are the first to describe a link between NASH, the function of UCEs, and hyperammonemia, providing a novel therapeutic target. LAY SUMMARY In patients with fatty liver disease, the enzymes that convert nitrogen waste into urea may be affected, leading to the accumulation of ammonia, which is toxic. This accumulation of ammonia can lead to scar tissue development, increasing the risk of disease progression. In this study, we show that fat accumulation in the liver produces a reversible reduction in the function of the enzymes that are involved in detoxification of ammonia. These data provide potential new targets for the treatment of fatty liver disease.
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Hasenan SM, Karsani SA, Jubri Z. Modulation of age related protein expression changes by gelam honey in cardiac mitochondrial rats. Exp Gerontol 2018; 113:1-9. [PMID: 30248357 DOI: 10.1016/j.exger.2018.09.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 09/04/2018] [Accepted: 09/06/2018] [Indexed: 12/14/2022]
Abstract
Aging is characterized by progressive decline in biochemical and physiological functions. According to the free radical theory of aging, aging results from oxidative damage due to the accumulation of excess reactive oxygen species (ROS). Mitochondria are the main source of ROS production and are also the main target for ROS. Therefore, a diet high in antioxidant such as honey is potentially able to protect the body from ROS and oxidative damage. Gelam honey is higher in flavonoid content and phenolic compounds compared to other local honey. This study was conducted to determine the effects of gelam honey on age related protein expression changes in cardiac mitochondrial rat. A total of 24 Sprague-Dawley male rats were divided into two groups: the young group (2 months old), and aged group (19 months old). Each group were then subdivided into two groups: control group (force-fed with distilled water), and treatment group (force-fed with gelam honey, 2.5 g/kg), and were treated for 8 months. Comparative proteomic analysis of mitochondria from cardiac tissue was then performed by high performance mass spectrometry (Q-TOF LCMS/MS) followed by validation of selected proteins by Western blotting. Proteins were identified using Spectrum Mill software and were subjected to stringent statistical analysis. A total of 286 proteins were identified in the young control group (YC) and 241 proteins were identified in the young gelam group (YG). In the aged group, a total of 243 proteins were identified in control group (OC), and 271 proteins in gelam group (OG). Comparative proteome profiling identified 69 proteins with different abundance (p < 0.05) in OC when compared to YC, and also in YG when compared to YC. On the other hand, 55 proteins were found to be different in abundance when comparing OG with OC. In the aged group, gelam honey supplementation affected the relative abundance of 52 proteins with most of these proteins showing a decrease in the control group. Bioinformatics analysis showed that the majority of the affected proteins were involved in the respiratory chain (OXPHOS) which play an important role in maintaining mitochondrial function.
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Affiliation(s)
- Siti Maisarah Hasenan
- Department of Biochemistry, Medical Centre of National University of Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000, Cheras, Kuala Lumpur, Malaysia
| | - Saiful Anuar Karsani
- Institute of Biological Sciences, Faculty of Science, University of Malaya and University of Malaya Centre for Proteomics Research (UMCPR), Kuala Lumpur, Malaysia.
| | - Zakiah Jubri
- Department of Biochemistry, Medical Centre of National University of Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000, Cheras, Kuala Lumpur, Malaysia.
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Sarmah D, Kaur H, Saraf J, Vats K, Pravalika K, Wanve M, Kalia K, Borah A, Kumar A, Wang X, Yavagal DR, Dave KR, Bhattacharya P. Mitochondrial Dysfunction in Stroke: Implications of Stem Cell Therapy. Transl Stroke Res 2018; 10:10.1007/s12975-018-0642-y. [PMID: 29926383 DOI: 10.1007/s12975-018-0642-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 05/21/2018] [Accepted: 06/12/2018] [Indexed: 01/06/2023]
Abstract
Stroke is a debilitating condition which is also the second leading cause of death and disability worldwide. Despite the benefits and promises shown by numerous neuroprotective agents in animal stroke models, their clinical translation has not been a complete success. Hence, search for treatment options have directed researchers towards utilising stem cells. Mitochondria has a major involvement in the pathophysiology of stroke and a number of other conditions. Stem cells have shown the ability to transfer mitochondria to the damaged cells and to help revive cell energetics in the recipient cell. The present review discusses how stem cells could be employed to protect neurons and mitochondria in stroke and also the various mechanisms involved in neuroprotection.
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Affiliation(s)
- Deepaneeta Sarmah
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Harpreet Kaur
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Jackson Saraf
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Kanchan Vats
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Kanta Pravalika
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Madhuri Wanve
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Kiran Kalia
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Akhilesh Kumar
- Department of Botany, Banaras Hindu University, Varanasi, India
| | - Xin Wang
- Department of Neurosurgery, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
| | - Dileep R Yavagal
- Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Kunjan R Dave
- Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Pallab Bhattacharya
- Department or Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Gandhinagar, 382355, Gujarat, India.
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Valvassori SS, Bavaresco DV, Feier G, Cechinel-Recco K, Steckert AV, Varela RB, Borges C, Carvalho-Silva M, Gomes LM, Streck EL, Quevedo J. Increased oxidative stress in the mitochondria isolated from lymphocytes of bipolar disorder patients during depressive episodes. Psychiatry Res 2018; 264:192-201. [PMID: 29653348 DOI: 10.1016/j.psychres.2018.03.089] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 02/19/2018] [Accepted: 03/31/2018] [Indexed: 10/25/2022]
Abstract
The present study aims to investigate the oxidative stress parameters in isolated mitochondria, as well as looking at mitochondrial complex activity in patients with Bipolar Disorder (BD) during depressive or euthymic episodes. This study evaluated the levels of mitochondrial complex (I, II, II-III and IV) activity in lymphocytes from BD patients. We evaluated the following oxidative stress parameters: superoxide, thiobarbituric acid reactive species (TBARS) and carbonyl levels in submitochondrial particles of lymphocytes from bipolar patients. 51 bipolar patients were recruited into this study: 34 in the euthymic phase, and 17 in the depressive phase. Our results indicated that the depressive phase could increase the levels of mitochondrial superoxide, carbonyl and TBARS, and superoxide dismutase, and could decrease the levels of mitochondrial complex II activity in the lymphocytes of bipolar patients. It was also observed that there was a negative correlation between the Hamilton Depression Rating Scale (HDRS) and complex II activity in the lymphocytes of depressive bipolar patients. In addition, there was a positive correlation between HDRS and superoxide, superoxide dismutase, TBARS and carbonyl. Additionally, there was a negative correlation between complex II activity and oxidative stress parameters. In conclusion, our results suggest that mitochondrial oxidative stress and mitochondrial complex II dysfunction play important roles in the depressive phase of BD.
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Affiliation(s)
- Samira S Valvassori
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil.
| | - Daniela V Bavaresco
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Gustavo Feier
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Kelen Cechinel-Recco
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Amanda V Steckert
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Roger B Varela
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Cenita Borges
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Milena Carvalho-Silva
- Experimental Neurology Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Lara M Gomes
- Experimental Neurology Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Emílio L Streck
- Experimental Neurology Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - João Quevedo
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil; Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA; Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA; Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
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Regulation of mitochondrial respiration and ATP synthesis via cytochrome c oxidase. RENDICONTI LINCEI-SCIENZE FISICHE E NATURALI 2018. [DOI: 10.1007/s12210-018-0710-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Srinivas Bharath MM. Post-Translational Oxidative Modifications of Mitochondrial Complex I (NADH: Ubiquinone Oxidoreductase): Implications for Pathogenesis and Therapeutics in Human Diseases. J Alzheimers Dis 2018; 60:S69-S86. [PMID: 28582861 DOI: 10.3233/jad-170117] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mitochondrial complex I (NADH: ubiquinone oxidoreductase; CI) is central to the electron transport chain (ETC), oxidative phosphorylation, and ATP production in eukaryotes. CI is a multi-subunit complex with a complicated yet organized structure that optimally connects electron transfer with proton translocation and forms higher-order supercomplexes with other ETC complexes. Efforts to understand the molecular genetics, expression profile of subunits, and structure-function relationship of CI have increased over the years due to the direct role of the complex in human diseases. Although mutations in the nuclear and mitochondrial genes of CI and altered expression of subunits could potentially lower CI activity leading to mitochondrial dysfunction in many diseases, oxidative post-translational modifications (PTMs) have emerged as an important mechanism contributing to altered CI activity. These mainly include reversible and irreversible cysteine modifications, tyrosine nitration, carbonylation, and tryptophan oxidation that are generated following exposure to reactive oxygen species/reactive nitrogen species. Interestingly, oxidative PTMs could contribute either to CI damage, mitochondrial dysfunction, and ensuing cell death or a response mechanism with potential cytoprotective effects. This has also emerged as a promising field for structural biologists since analysis of PTMs could assist in understanding the structure-function relationship of the complex and correlate electron transfer mechanism with energy production. However, analysis of PTMs of CI and their contribution to CI function are incomplete in many physiological and pathological conditions. This review aims to highlight the role of oxidative PTMs in modulating CI activity with implications toward pathobiology of CNS diseases and novel therapeutics.
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Affiliation(s)
- M M Srinivas Bharath
- Department of Neurochemistry and Neurotoxicology Laboratory at the Neurobiology Research Center, National Institute of Mental Health and Neurosciences, Bangalore, India
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49
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Bruni F, Di Meo I, Bellacchio E, Webb BD, McFarland R, Chrzanowska‐Lightowlers ZM, He L, Skorupa E, Moroni I, Ardissone A, Walczak A, Tyynismaa H, Isohanni P, Mandel H, Prokisch H, Haack T, Bonnen PE, Enrico B, Pronicka E, Ghezzi D, Taylor RW, Diodato D. Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease. Hum Mutat 2018; 39:563-578. [PMID: 29314548 PMCID: PMC5873438 DOI: 10.1002/humu.23398] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 12/21/2017] [Accepted: 12/28/2017] [Indexed: 01/17/2023]
Abstract
In recent years, an increasing number of mitochondrial disorders have been associated with mutations in mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs), which are key enzymes of mitochondrial protein synthesis. Bi-allelic functional variants in VARS2, encoding the mitochondrial valyl tRNA-synthetase, were first reported in a patient with psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) Complex I defect, before being described in a patient with a neonatal form of encephalocardiomyopathy. Here we provide a detailed genetic, clinical, and biochemical description of 13 patients, from nine unrelated families, harboring VARS2 mutations. All patients except one, who manifested with a less severe disease course, presented at birth exhibiting severe encephalomyopathy and cardiomyopathy. Features included hypotonia, psychomotor delay, seizures, feeding difficulty, abnormal cranial MRI, and elevated lactate. The biochemical phenotype comprised a combined Complex I and Complex IV OXPHOS defect in muscle, with patient fibroblasts displaying normal OXPHOS activity. Homology modeling supported the pathogenicity of VARS2 missense variants. The detailed description of this cohort further delineates our understanding of the clinical presentation associated with pathogenic VARS2 variants and we recommend that this gene should be considered in early-onset mitochondrial encephalomyopathies or encephalocardiomyopathies.
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Affiliation(s)
- Francesco Bruni
- Wellcome Centre for Mitochondrial ResearchInstitute of NeuroscienceNewcastle UniversityNewcastle upon TyneUnited Kingdom
| | - Ivano Di Meo
- Molecular Neurogenetics UnitFoundation IRCCS Neurological Institute C. BestaMilanItaly
| | - Emanuele Bellacchio
- Genetics and Rare DiseasesResearch Division‘Bambino Gesù’ Children HospitalRomeItaly
| | - Bryn D. Webb
- Department of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew YorkNew York
| | - Robert McFarland
- Wellcome Centre for Mitochondrial ResearchInstitute of NeuroscienceNewcastle UniversityNewcastle upon TyneUnited Kingdom
| | | | - Langping He
- Wellcome Centre for Mitochondrial ResearchInstitute of NeuroscienceNewcastle UniversityNewcastle upon TyneUnited Kingdom
| | - Ewa Skorupa
- Department of BiochemistryRadioimmunology and Experimental MedicineThe Children's Memorial Health InstituteWarsawPoland
| | - Isabella Moroni
- Child Neurology UnitFoundation IRCCS Neurological Institute “C. Besta”MilanItaly
| | - Anna Ardissone
- Molecular Neurogenetics UnitFoundation IRCCS Neurological Institute C. BestaMilanItaly
- Child Neurology UnitFoundation IRCCS Neurological Institute “C. Besta”MilanItaly
- Department of Molecular and Translational Medicine DIMETUniversity of Milan‐BicoccaMilanItaly
| | - Anna Walczak
- Department of Medical GeneticsCentre of BiostructureMedical University of WarsawWarsawPoland
| | - Henna Tyynismaa
- Research Programs UnitMolecular NeurologyUniversity of HelsinkiHelsinkiFinland
| | - Pirjo Isohanni
- Research Programs UnitMolecular NeurologyUniversity of HelsinkiHelsinkiFinland
- Department of Pediatric NeurologyChildren's HospitalUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
| | - Hanna Mandel
- Institute of Human Genetics and Metabolic DiseasesGalilee Medical CenterNahariyaIsrael
| | - Holger Prokisch
- Institute of Human GeneticsTechnische Universität MünchenMunichGermany
- Institute of Human GeneticsHelmholtz Zentrum MünchenNeuherbergGermany
| | - Tobias Haack
- Institute of Human GeneticsHelmholtz Zentrum MünchenNeuherbergGermany
| | - Penelope E. Bonnen
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas
| | - Bertini Enrico
- Unit of Neuromuscular and Neurodegenerative DisordersLaboratory of Molecular Medicine‘Bambino Ges.’ Children's Research HospitalRomeItaly
| | - Ewa Pronicka
- Department of PediatricsNutrition and Metabolic DiseasesThe Children's Memorial Health InstituteWarsawPoland
| | - Daniele Ghezzi
- Molecular Neurogenetics UnitFoundation IRCCS Neurological Institute C. BestaMilanItaly
- Department of Pathophysiology and TransplantationUniversity of MilanMilanItaly
| | - Robert W. Taylor
- Wellcome Centre for Mitochondrial ResearchInstitute of NeuroscienceNewcastle UniversityNewcastle upon TyneUnited Kingdom
| | - Daria Diodato
- Unit of Neuromuscular and Neurodegenerative DisordersLaboratory of Molecular Medicine‘Bambino Ges.’ Children's Research HospitalRomeItaly
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50
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Aich A, Wang C, Chowdhury A, Ronsör C, Pacheu-Grau D, Richter-Dennerlein R, Dennerlein S, Rehling P. COX16 promotes COX2 metallation and assembly during respiratory complex IV biogenesis. eLife 2018; 7:32572. [PMID: 29381136 PMCID: PMC5809144 DOI: 10.7554/elife.32572] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 01/14/2018] [Indexed: 12/25/2022] Open
Abstract
Cytochrome c oxidase of the mitochondrial oxidative phosphorylation system reduces molecular oxygen with redox equivalent-derived electrons. The conserved mitochondrial-encoded COX1- and COX2-subunits are the heme- and copper-center containing core subunits that catalyze water formation. COX1 and COX2 initially follow independent biogenesis pathways creating assembly modules with subunit-specific, chaperone-like assembly factors that assist in redox centers formation. Here, we find that COX16, a protein required for cytochrome c oxidase assembly, interacts specifically with newly synthesized COX2 and its copper center-forming metallochaperones SCO1, SCO2, and COA6. The recruitment of SCO1 to the COX2-module is COX16- dependent and patient-mimicking mutations in SCO1 affect interaction with COX16. These findings implicate COX16 in CuA-site formation. Surprisingly, COX16 is also found in COX1-containing assembly intermediates and COX2 recruitment to COX1. We conclude that COX16 participates in merging the COX1 and COX2 assembly lines.
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Affiliation(s)
- Abhishek Aich
- Department of Cellular Biochemistry, University Medical Centre Göttingen, Göttingen, Germany
| | - Cong Wang
- Department of Cellular Biochemistry, University Medical Centre Göttingen, Göttingen, Germany
| | - Arpita Chowdhury
- Department of Cellular Biochemistry, University Medical Centre Göttingen, Göttingen, Germany
| | - Christin Ronsör
- Department of Cellular Biochemistry, University Medical Centre Göttingen, Göttingen, Germany
| | - David Pacheu-Grau
- Department of Cellular Biochemistry, University Medical Centre Göttingen, Göttingen, Germany
| | | | - Sven Dennerlein
- Department of Cellular Biochemistry, University Medical Centre Göttingen, Göttingen, Germany
| | - Peter Rehling
- Department of Cellular Biochemistry, University Medical Centre Göttingen, Göttingen, Germany.,Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
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