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Luo L, Wang M, Liu Y, Li J, Bu F, Yuan H, Tang R, Liu C, He G. Sequencing and characterizing human mitochondrial genomes in the biobank-based genomic research paradigm. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1610-1625. [PMID: 39843848 DOI: 10.1007/s11427-024-2736-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 09/18/2024] [Indexed: 01/24/2025]
Abstract
Human mitochondrial DNA (mtDNA) harbors essential mutations linked to aging, neurodegenerative diseases, and complex muscle disorders. Due to its uniparental and haploid inheritance, mtDNA captures matrilineal evolutionary trajectories, playing a crucial role in population and medical genetics. However, critical questions about the genomic diversity patterns, inheritance models, and evolutionary and medical functions of mtDNA remain unresolved or underexplored, particularly in the transition from traditional genotyping to large-scale genomic analyses. This review summarizes recent advancements in data-driven genomic research and technological innovations that address these questions and clarify the biological impact of nuclear-mitochondrial segments (NUMTs) and mtDNA variants on human health, disease, and evolution. We propose a streamlined pipeline to comprehensively identify mtDNA and NUMT genomic diversity using advanced sequencing and computational technologies. Haplotype-resolved mtDNA sequencing and assembly can distinguish authentic mtDNA variants from NUMTs, reduce diagnostic inaccuracies, and provide clearer insights into heteroplasmy patterns and the authenticity of paternal inheritance. This review emphasizes the need for integrative multi-omics approaches and emerging long-read sequencing technologies to gain new insights into mutation mechanisms, the influence of heteroplasmy and paternal inheritance on mtDNA diversity and disease susceptibility, and the detailed functions of NUMTs.
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Affiliation(s)
- Lintao Luo
- Institute of Rare Diseases, West China Hospital of Sichuan University, Sichuan University, Chengdu, 610000, China
- Department of Forensic Medicine, College of Basic Medicine, Chongqing Medical University, Chongqing, 400331, China
| | - Mengge Wang
- Institute of Rare Diseases, West China Hospital of Sichuan University, Sichuan University, Chengdu, 610000, China.
- Center for Archaeological Science, Sichuan University, Chengdu, 610000, China.
- Anti-Drug Technology Center of Guangdong Province, Guangzhou, 510230, China.
| | - Yunhui Liu
- Institute of Rare Diseases, West China Hospital of Sichuan University, Sichuan University, Chengdu, 610000, China
- Department of Forensic Medicine, College of Basic Medicine, Chongqing Medical University, Chongqing, 400331, China
| | - Jianbo Li
- Department of Forensic Medicine, College of Basic Medicine, Chongqing Medical University, Chongqing, 400331, China
| | - Fengxiao Bu
- Institute of Rare Diseases, West China Hospital of Sichuan University, Sichuan University, Chengdu, 610000, China
- Center for Archaeological Science, Sichuan University, Chengdu, 610000, China
| | - Huijun Yuan
- Institute of Rare Diseases, West China Hospital of Sichuan University, Sichuan University, Chengdu, 610000, China.
- Center for Archaeological Science, Sichuan University, Chengdu, 610000, China.
| | - Renkuan Tang
- Department of Forensic Medicine, College of Basic Medicine, Chongqing Medical University, Chongqing, 400331, China.
| | - Chao Liu
- Department of Forensic Medicine, College of Basic Medicine, Chongqing Medical University, Chongqing, 400331, China.
- Anti-Drug Technology Center of Guangdong Province, Guangzhou, 510230, China.
| | - Guanglin He
- Institute of Rare Diseases, West China Hospital of Sichuan University, Sichuan University, Chengdu, 610000, China.
- Center for Archaeological Science, Sichuan University, Chengdu, 610000, China.
- Anti-Drug Technology Center of Guangdong Province, Guangzhou, 510230, China.
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2
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Zhang H, Meléndez A. Conserved components of the macroautophagy machinery in Caenorhabditis elegans. Genetics 2025; 229:iyaf007. [PMID: 40180610 PMCID: PMC12005284 DOI: 10.1093/genetics/iyaf007] [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: 03/29/2024] [Accepted: 12/13/2024] [Indexed: 04/05/2025] Open
Abstract
Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane autophagosome and its subsequent delivery to lysosomes for degradation and recycling. In Caenorhabditis elegans, autophagy participates in diverse processes such as stress resistance, cell fate specification, tissue remodeling, aging, and adaptive immunity. Genetic screens in C. elegans have identified a set of metazoan-specific autophagy genes that form the basis for our molecular understanding of steps unique to the autophagy pathway in multicellular organisms. Suppressor screens have uncovered multiple mechanisms that modulate autophagy activity under physiological conditions. C. elegans also provides a model to investigate how autophagy activity is coordinately controlled at an organismal level. In this chapter, we will discuss the molecular machinery, regulation, and physiological functions of autophagy, and also methods utilized for monitoring autophagy during C. elegans development.
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Affiliation(s)
- Hong Zhang
- National Laboratory of Biomacromolecules, New Cornerstone Science Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Alicia Meléndez
- Department of Biology, Queens College, City University of New York, Flushing, NY 11367, USA
- Molecular, Cellular and Developmental Biology and Biochemistry Ph.D. Programs, The Graduate Center of the City University of New York, New York, NY 10016, USA
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3
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King DE, Copeland WC. DNA repair pathways in the mitochondria. DNA Repair (Amst) 2025; 146:103814. [PMID: 39914164 PMCID: PMC11848857 DOI: 10.1016/j.dnarep.2025.103814] [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: 11/26/2024] [Revised: 01/14/2025] [Accepted: 01/28/2025] [Indexed: 02/24/2025]
Abstract
Mitochondria contain their own small, circular genome that is present in high copy number. The mitochondrial genome (mtDNA) encodes essential subunits of the electron transport chain. Mutations in the mitochondrial genome are associated with a wide range of mitochondrial diseases and the maintenance and replication of mtDNA is crucial to cellular health. Despite the importance of maintaining mtDNA genomic integrity, fewer DNA repair pathways exist in the mitochondria than in the nucleus. However, mitochondria have numerous pathways that allow for the removal and degradation of DNA damage that may prevent accumulation of mutations. Here, we briefly review the DNA repair pathways present in the mitochondria, sources of mtDNA mutations, and discuss the passive role that mtDNA mutagenesis may play in cancer progression.
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Affiliation(s)
- Dillon E King
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States
| | - William C Copeland
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States.
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4
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Forbes KJ, Barrera MA, Nielsen-Roine K, Hersh EW, Janes JK, Harrower WL, Gorrell JC. Stabilizing selection and mitochondrial heteroplasmy in the Canada lynx ( Lynx canadensis). Genome 2024; 67:493-502. [PMID: 39226612 DOI: 10.1139/gen-2023-0094] [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: 09/05/2024]
Abstract
Mitochondrial DNA is commonly used in population genetic studies to investigate spatial structure, intraspecific variation, and phylogenetic relationships. The control region is the most rapidly evolving and largest non-coding region, but its analysis can be complicated by heteroplasmic signals of genome duplication in many mammals, including felids. Here, we describe the presence of heteroplasmy in the control region of Canada lynx (Lynx canadensis) through intra-individual sequence variation. Our results demonstrate multiple haplotypes of varying length in each lynx, resulting from different copy numbers of the repetitive sequence RS-2 and suggest possible heteroplasmic single nucleotide polymorphisms in both repetitive sequences RS-2 and RS-3. Intra-individual variation was only observed in the repetitive sequences while inter-individual variation was detected in the flanking regions outside of the repetitive sequences, indicating that heteroplasmic mutations are restricted to these repeat regions. Although each lynx displayed multiple haplotypes of varying length, we found the most common variant contained three complete copies of the RS-2 repeat unit, suggesting copy number is regulated by stabilizing selection. While genome duplication offers potential for increased diversity, heteroplasmy may lead to a selective advantage or detriment in the face of mitochondrial function and disease, which could have significant implications for wildlife populations experiencing decline (e.g., bottlenecks) as a result of habitat modification or climate change.
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Affiliation(s)
- Krystyn J Forbes
- Biology Department, Vancouver Island University, 900 Fifth Street, Nanaimo, BC V9R 5S5, Canada
| | - McIntyre A Barrera
- Biology Department, Vancouver Island University, 900 Fifth Street, Nanaimo, BC V9R 5S5, Canada
| | - Karsten Nielsen-Roine
- Biology Department, Vancouver Island University, 900 Fifth Street, Nanaimo, BC V9R 5S5, Canada
| | - Evan W Hersh
- Biology Department, Vancouver Island University, 900 Fifth Street, Nanaimo, BC V9R 5S5, Canada
| | - Jasmine K Janes
- Biology Department, Vancouver Island University, 900 Fifth Street, Nanaimo, BC V9R 5S5, Canada
- Ecosystem Science and Management, University of Northern British Columbia, 3333 University Way, Prince George, BC V2N 4Z9, Canada
- Species Survival Commission, Orchid Specialist Group, IUCN North America, Washington, DC, USA
| | - William L Harrower
- Department of Forest and Conservation Sciences, The University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Jamieson C Gorrell
- Biology Department, Vancouver Island University, 900 Fifth Street, Nanaimo, BC V9R 5S5, Canada
- Ecosystem Science and Management, University of Northern British Columbia, 3333 University Way, Prince George, BC V2N 4Z9, Canada
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5
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Nie Q, Zhang W, Lin S, Huang M, Li Y, Qiu Y, Li J, Chen X, Wang Y, Tong X, Wu J, He P, Cai Q, Chen L, Chen M, Guo W, Lin Y, Yu L, Hou J, Cai W, Chen H, Wang C, Fu F. Identification of sequence polymorphism in the D-loop region of mitochondrial DNA as a risk factor for breast cancer. Cancer Sci 2024; 115:4064-4073. [PMID: 39401980 PMCID: PMC11611757 DOI: 10.1111/cas.16353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 08/23/2024] [Accepted: 09/08/2024] [Indexed: 12/06/2024] Open
Abstract
Mitochondrial DNA (mtDNA) variations affect the efficiency of the electron transport chain and production of reactive oxygen species, contributing to carcinogenesis. The D-loop region of mtDNA has emerged as a variation hotspot region in human neoplasia; however, the potential contribution of these variations in breast cancer risk prediction remains unknown. We investigated the relationship between germline single nucleotide polymorphisms (SNPs) in the entire D-loop region and breast cancer risk in Chinese women. Peripheral blood-isolated mtDNA from 2329 patients with breast cancer and 2328 cancer-free controls was examined for SNPs. In the combined cohort, we used traditional risk factors, susceptibility germline polymorphisms, and logistic regression analysis to evaluate the predictive value of susceptibility variants for breast cancer risk. We calculated the area under the receiver operating characteristic curve (AUC) as a measure. We also measured the content of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Individual polymorphisms SNP573 were significantly associated with breast cancer risk in both the discovery and validation cohorts. In the combined cohort, the AUC of the traditional risk factors was 64.3%; after adding susceptibility variants, the AUC was 64.9% (DeLong test, p = 0.007). 8-OHdG levels were significantly higher in patients with breast cancer than in controls and higher in individuals with SNP573 than in those negative for this variation. Overall, oxidative stress might be associated with the risk of breast cancer, and SNP573 might be associated with oxidative stress. Our results indicate the risk potential of polymorphisms in the D-loop region in breast cancer in Southern China.
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6
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Zhang Y, Liu L, Yue L, Huang Y, Wang B, Liu P. Uncovering key mechanisms and intervention therapies in aging skin. Cytokine Growth Factor Rev 2024; 79:66-80. [PMID: 39198086 DOI: 10.1016/j.cytogfr.2024.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 07/31/2024] [Indexed: 09/01/2024]
Abstract
Advancements in understanding skin aging mechanisms, which encompass both external and internal aging processes, have spurred the development of innovative treatments primarily aimed at improving cosmetic appearance. These findings offer the potential for the development of novel therapeutic strategies aimed at achieving long-term, non-therapy-dependent clinical benefits, including the reversal of aging and the mitigation of associated health conditions. Realizing this goal requires further research to establish the safety and efficacy of targeting aging-related skin changes, such as pigmentation, wrinkling, and collagen loss. Systematic investigation is needed to identify the most effective interventions and determine optimal anti-aging treatment strategies. These reviews highlight the features and possible mechanisms of skin aging, as well as the latest progress and future direction of skin aging research, to provide a theoretical basis for new practical anti-skin aging strategies.
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Affiliation(s)
- Yuqin Zhang
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, PR China
| | - Lin Liu
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, PR China
| | - Lixia Yue
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Yongzhuo Huang
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, PR China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
| | - Bing Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, PR China.
| | - Peifeng Liu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, PR China.
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7
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Cerantonio A, Citrigno L, Greco BM, De Benedittis S, Passarino G, Maletta R, Qualtieri A, Montesanto A, Spadafora P, Cavalcanti F. The Role of Mitochondrial Copy Number in Neurodegenerative Diseases: Present Insights and Future Directions. Int J Mol Sci 2024; 25:6062. [PMID: 38892250 PMCID: PMC11172615 DOI: 10.3390/ijms25116062] [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: 04/30/2024] [Revised: 05/21/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
Neurodegenerative diseases are progressive disorders that affect the central nervous system (CNS) and represent the major cause of premature death in the elderly. One of the possible determinants of neurodegeneration is the change in mitochondrial function and content. Altered levels of mitochondrial DNA copy number (mtDNA-CN) in biological fluids have been reported during both the early stages and progression of the diseases. In patients affected by neurodegenerative diseases, changes in mtDNA-CN levels appear to correlate with mitochondrial dysfunction, cognitive decline, disease progression, and ultimately therapeutic interventions. In this review, we report the main results published up to April 2024, regarding the evaluation of mtDNA-CN levels in blood samples from patients affected by Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). The aim is to show a probable link between mtDNA-CN changes and neurodegenerative disorders. Understanding the causes underlying this association could provide useful information on the molecular mechanisms involved in neurodegeneration and offer the development of new diagnostic approaches and therapeutic interventions.
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Affiliation(s)
- Annamaria Cerantonio
- Institute for Biomedical Research and Innovation, National Research Council (IRIB-CNR), 87050 Mangone, CS, Italy; (A.C.); (P.S.)
| | - Luigi Citrigno
- Institute for Biomedical Research and Innovation, National Research Council (IRIB-CNR), 87050 Mangone, CS, Italy; (A.C.); (P.S.)
| | - Beatrice Maria Greco
- Institute for Biomedical Research and Innovation, National Research Council (IRIB-CNR), 87050 Mangone, CS, Italy; (A.C.); (P.S.)
- Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, CS, Italy
| | - Selene De Benedittis
- Institute for Biomedical Research and Innovation, National Research Council (IRIB-CNR), 87050 Mangone, CS, Italy; (A.C.); (P.S.)
| | - Giuseppe Passarino
- Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, CS, Italy
| | - Raffaele Maletta
- Regional Neurogenetic Centre (CRN), Department of Primary Care, ASP Catanzaro, 88046 Lamezia Terme, CZ, Italy
- Association for Neurogenetic Research (ARN), 88046 Lamezia Terme, CZ, Italy
| | - Antonio Qualtieri
- Institute for Biomedical Research and Innovation, National Research Council (IRIB-CNR), 87050 Mangone, CS, Italy; (A.C.); (P.S.)
| | - Alberto Montesanto
- Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, CS, Italy
| | - Patrizia Spadafora
- Institute for Biomedical Research and Innovation, National Research Council (IRIB-CNR), 87050 Mangone, CS, Italy; (A.C.); (P.S.)
| | - Francesca Cavalcanti
- Institute for Biomedical Research and Innovation, National Research Council (IRIB-CNR), 87050 Mangone, CS, Italy; (A.C.); (P.S.)
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8
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Bartman S, Coppotelli G, Ross JM. Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases. Curr Issues Mol Biol 2024; 46:1987-2026. [PMID: 38534746 DOI: 10.3390/cimb46030130] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 02/27/2024] [Accepted: 02/28/2024] [Indexed: 03/28/2024] Open
Abstract
Mitochondria are thought to have become incorporated within the eukaryotic cell approximately 2 billion years ago and play a role in a variety of cellular processes, such as energy production, calcium buffering and homeostasis, steroid synthesis, cell growth, and apoptosis, as well as inflammation and ROS production. Considering that mitochondria are involved in a multitude of cellular processes, mitochondrial dysfunction has been shown to play a role within several age-related diseases, including cancers, diabetes (type 2), and neurodegenerative diseases, although the underlying mechanisms are not entirely understood. The significant increase in lifespan and increased incidence of age-related diseases over recent decades has confirmed the necessity to understand the mechanisms by which mitochondrial dysfunction impacts the process of aging and age-related diseases. In this review, we will offer a brief overview of mitochondria, along with structure and function of this important organelle. We will then discuss the cause and consequence of mitochondrial dysfunction in the aging process, with a particular focus on its role in inflammation, cognitive decline, and neurodegenerative diseases, such as Huntington's disease, Parkinson's disease, and Alzheimer's disease. We will offer insight into therapies and interventions currently used to preserve or restore mitochondrial functioning during aging and neurodegeneration.
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Affiliation(s)
- Sydney Bartman
- George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
| | - Giuseppe Coppotelli
- George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
| | - Jaime M Ross
- George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
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9
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Del Dotto V, Musiani F, Baracca A, Solaini G. Variants in Human ATP Synthase Mitochondrial Genes: Biochemical Dysfunctions, Associated Diseases, and Therapies. Int J Mol Sci 2024; 25:2239. [PMID: 38396915 PMCID: PMC10889682 DOI: 10.3390/ijms25042239] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 02/06/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
Mitochondrial ATP synthase (Complex V) catalyzes the last step of oxidative phosphorylation and provides most of the energy (ATP) required by human cells. The mitochondrial genes MT-ATP6 and MT-ATP8 encode two subunits of the multi-subunit Complex V. Since the discovery of the first MT-ATP6 variant in the year 1990 as the cause of Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome, a large and continuously increasing number of inborn variants in the MT-ATP6 and MT-ATP8 genes have been identified as pathogenic. Variants in these genes correlate with various clinical phenotypes, which include several neurodegenerative and multisystemic disorders. In the present review, we report the pathogenic variants in mitochondrial ATP synthase genes and highlight the molecular mechanisms underlying ATP synthase deficiency that promote biochemical dysfunctions. We discuss the possible structural changes induced by the most common variants found in patients by considering the recent cryo-electron microscopy structure of human ATP synthase. Finally, we provide the state-of-the-art of all therapeutic proposals reported in the literature, including drug interventions targeting mitochondrial dysfunctions, allotopic gene expression- and nuclease-based strategies, and discuss their potential translation into clinical trials.
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Affiliation(s)
- Valentina Del Dotto
- Laboratory of Biochemistry and Mitochondrial Pathophysiology, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (V.D.D.); (G.S.)
| | - Francesco Musiani
- Laboratory of Bioinorganic Chemistry, Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40127 Bologna, Italy;
| | - Alessandra Baracca
- Laboratory of Biochemistry and Mitochondrial Pathophysiology, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (V.D.D.); (G.S.)
| | - Giancarlo Solaini
- Laboratory of Biochemistry and Mitochondrial Pathophysiology, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (V.D.D.); (G.S.)
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10
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Ali MA, Gioscia-Ryan R, Yang D, Sutton NR, Tyrrell DJ. Cardiovascular aging: spotlight on mitochondria. Am J Physiol Heart Circ Physiol 2024; 326:H317-H333. [PMID: 38038719 PMCID: PMC11219063 DOI: 10.1152/ajpheart.00632.2023] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/28/2023] [Accepted: 11/29/2023] [Indexed: 12/02/2023]
Abstract
Mitochondria are cellular organelles critical for ATP production and are particularly relevant to cardiovascular diseases including heart failure, atherosclerosis, ischemia-reperfusion injury, and cardiomyopathies. With advancing age, even in the absence of clinical disease, mitochondrial homeostasis becomes disrupted (e.g., redox balance, mitochondrial DNA damage, oxidative metabolism, and mitochondrial quality control). Mitochondrial dysregulation leads to the accumulation of damaged and dysfunctional mitochondria, producing excessive reactive oxygen species and perpetuating mitochondrial dysfunction. In addition, mitochondrial DNA, cardiolipin, and N-formyl peptides are potent activators of cell-intrinsic and -extrinsic inflammatory pathways. These age-related mitochondrial changes contribute to the development of cardiovascular diseases. This review covers the impact of aging on mitochondria and links these mechanisms to therapeutic implications for age-associated cardiovascular diseases.
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Affiliation(s)
- Md Akkas Ali
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Rachel Gioscia-Ryan
- Department of Anesthesiology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, United States
| | - Dongli Yang
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Nadia R Sutton
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States
| | - Daniel J Tyrrell
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States
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11
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Karimi N. Approaches in line with human physiology to prevent skin aging. Front Physiol 2023; 14:1279371. [PMID: 37954446 PMCID: PMC10634238 DOI: 10.3389/fphys.2023.1279371] [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: 08/17/2023] [Accepted: 10/16/2023] [Indexed: 11/14/2023] Open
Abstract
Skin aging is a complex process that is influenced by intrinsic and extrinsic factors that impact the skin's protective functions and overall health. As the body's outermost layer, the skin plays a critical role in defending it against external threats, regulating body temperature, providing tactile sensation, and synthesizing vitamin D for bone health, immune function, and body homeostasis. However, as individuals age, the skin undergoes structural and functional changes, leading to impairments in these essential functions. In contemporary society, there is an increasing recognition of skin health as a significant indicator of overall wellbeing, resulting in a growing demand for anti-aging products and treatments. However, these products often have limitations in terms of safety, effective skin penetration, and potential systemic complications. To address these concerns, researchers are now focusing on approaches that are safer and better aligned with physiology of the skin. These approaches include adopting a proper diet and maintaining healthy lifestyle habits, the development of topical treatments that synchronize with the skin's circadian rhythm, utilizing endogenous antioxidant molecules, such as melatonin and natural products like polyphenols. Moreover, exploring alternative compounds for sun protection, such as natural ultraviolet (UV)-absorbing compounds, can offer safer options for shielding the skin from harmful radiation. Researchers are currently exploring the potential of adipose-derived stem cells, cell-free blood cell secretome (BCS) and other endogenous compounds for maintaining skin health. These approaches are more secure and more effective alternatives which are in line with human physiology to tackle skin aging. By emphasizing these innovative strategies, it is possible to develop effective treatments that not only slow down the skin aging process but also align better with the natural physiology of the skin. This review will focus on recent research in this field, highlighting the potential of these treatments as being safer and more in line with the skin's physiology in order to combat the signs of aging.
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Affiliation(s)
- Nazli Karimi
- Department of Physiology, Faculty of Medicine, Hacettepe University, Ankara, Türkiye
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12
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Gupta R, Kanai M, Durham TJ, Tsuo K, McCoy JG, Kotrys AV, Zhou W, Chinnery PF, Karczewski KJ, Calvo SE, Neale BM, Mootha VK. Nuclear genetic control of mtDNA copy number and heteroplasmy in humans. Nature 2023; 620:839-848. [PMID: 37587338 PMCID: PMC10447254 DOI: 10.1038/s41586-023-06426-5] [Citation(s) in RCA: 72] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 07/11/2023] [Indexed: 08/18/2023]
Abstract
Mitochondrial DNA (mtDNA) is a maternally inherited, high-copy-number genome required for oxidative phosphorylation1. Heteroplasmy refers to the presence of a mixture of mtDNA alleles in an individual and has been associated with disease and ageing. Mechanisms underlying common variation in human heteroplasmy, and the influence of the nuclear genome on this variation, remain insufficiently explored. Here we quantify mtDNA copy number (mtCN) and heteroplasmy using blood-derived whole-genome sequences from 274,832 individuals and perform genome-wide association studies to identify associated nuclear loci. Following blood cell composition correction, we find that mtCN declines linearly with age and is associated with variants at 92 nuclear loci. We observe that nearly everyone harbours heteroplasmic mtDNA variants obeying two principles: (1) heteroplasmic single nucleotide variants tend to arise somatically and accumulate sharply after the age of 70 years, whereas (2) heteroplasmic indels are maternally inherited as mixtures with relative levels associated with 42 nuclear loci involved in mtDNA replication, maintenance and novel pathways. These loci may act by conferring a replicative advantage to certain mtDNA alleles. As an illustrative example, we identify a length variant carried by more than 50% of humans at position chrM:302 within a G-quadruplex previously proposed to mediate mtDNA transcription/replication switching2,3. We find that this variant exerts cis-acting genetic control over mtDNA abundance and is itself associated in-trans with nuclear loci encoding machinery for this regulatory switch. Our study suggests that common variation in the nuclear genome can shape variation in mtCN and heteroplasmy dynamics across the human population.
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Affiliation(s)
- Rahul Gupta
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
| | - Masahiro Kanai
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Timothy J Durham
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Kristin Tsuo
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Jason G McCoy
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Anna V Kotrys
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Wei Zhou
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Patrick F Chinnery
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
| | - Konrad J Karczewski
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Sarah E Calvo
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Benjamin M Neale
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
| | - Vamsi K Mootha
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
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13
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Wang Y, Zhang X, Wang Z. Cellular barcoding: From developmental tracing to anti-tumor drug discovery. Cancer Lett 2023; 567:216281. [PMID: 37336285 DOI: 10.1016/j.canlet.2023.216281] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/31/2023] [Accepted: 06/10/2023] [Indexed: 06/21/2023]
Abstract
Clonal evolution has gained immense attention in explaining cancer cell status, history, and fate during cancer progression. Current single-cell or spatial transcriptome technologies have broadened our understanding of various mechanisms underlying cancer initiation, relapse, and drug resistance. However, technical challenges still hinder a better understanding of the dynamics of distinctive phenotypic states and abnormal trajectories from normal physiological transition to malignant stages. Cellular barcoding enabled lineage tracing on parallelly massive cells at single-cell resolution through different mechanisms lately, enabling new insights into exploring developmental trajectories, cancer progression, and targeted therapies. This review summarizes the latest noteworthy and robust strategies for different types of cellular barcodes. To introduce the major characteristics, advantages and limitations of these different strategies, this review will further guide in choosing or improving cellular barcoding technologies and their applications in cancer research.
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Affiliation(s)
- Yuqing Wang
- Medical Center of Hematology, The Second Affiliated Hospital, Army Medical University, Chongqing, 40037, China; State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, 40037, China
| | - Xi Zhang
- Medical Center of Hematology, The Second Affiliated Hospital, Army Medical University, Chongqing, 40037, China; State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, 40037, China; Jinfeng Laboratory, Chongqing, 401329, China.
| | - Zheng Wang
- Medical Center of Hematology, The Second Affiliated Hospital, Army Medical University, Chongqing, 40037, China; State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, 40037, China; Bio-Med Informatics Research Center & Clinical Research Center, The Second Affiliated Hospital, Army Medical University, Chongqing, 400037, China; Jinfeng Laboratory, Chongqing, 401329, China.
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14
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Françoso E, Zuntini AR, Ricardo PC, Araújo NS, Silva JPN, Brown MJF, Arias MC. The complete mitochondrial genome of Trigonisca nataliae (Hymenoptera, Apidae) assemblage reveals heteroplasmy in the control region. Gene 2023:147621. [PMID: 37419430 DOI: 10.1016/j.gene.2023.147621] [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: 04/25/2023] [Revised: 06/13/2023] [Accepted: 07/05/2023] [Indexed: 07/09/2023]
Abstract
The evolution of mitochondrial genomes in the stingless bees is surprisingly dynamic, making them a model system to understand mitogenome structure, function, and evolution. Out of the seven mitogenomes available in this group, five exhibit atypical characteristics, including extreme rearrangements, rapid evolution and complete mitogenome duplication. To further explore the mitogenome diversity in these bees, we utilized isolated mtDNA and Illumina sequencing to assemble the complete mitogenome of Trigonisca nataliae, a species found in Northern Brazil. The mitogenome of T. nataliae was highly conserved in gene content and structure when compared to Melipona species but diverged in the control region (CR). Using PCR amplification, cloning and Sanger sequencing, six different CR haplotypes, varying in size and content, were recovery. These findings indicate that heteroplasmy, where different mitochondrial haplotypes coexist within individuals, occurs in T. nataliae. Consequently, we argue that heteroplasmy might indeed be a common phenomenon in bees that could be associated with variations in mitogenome size and challenges encountered during the assembly process.
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Affiliation(s)
- Elaine Françoso
- Centre for Ecology, Evolution and Behaviour, Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, TW20 0EX, UK; Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, 05508-090, Brazil.
| | | | - Paulo Cseri Ricardo
- Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, 05508-090, Brazil
| | - Natália Souza Araújo
- Unit of Evolutionary Biology & Ecology, Université libre de Bruxelles (ULB), Brussels, Belgium
| | - João Paulo Naldi Silva
- Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, 05508-090, Brazil
| | - Mark J F Brown
- Centre for Ecology, Evolution and Behaviour, Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, TW20 0EX, UK
| | - Maria Cristina Arias
- Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, 05508-090, Brazil
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15
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Moradi Vastegani S, Nasrolahi A, Ghaderi S, Belali R, Rashno M, Farzaneh M, Khoshnam SE. Mitochondrial Dysfunction and Parkinson's Disease: Pathogenesis and Therapeutic Strategies. Neurochem Res 2023:10.1007/s11064-023-03904-0. [PMID: 36943668 DOI: 10.1007/s11064-023-03904-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 02/21/2023] [Accepted: 02/28/2023] [Indexed: 03/23/2023]
Abstract
Parkinson's disease (PD) is a common age-related neurodegenerative disorder whose pathogenesis is not completely understood. Mitochondrial dysfunction and increased oxidative stress have been considered as major causes and central events responsible for the progressive degeneration of dopaminergic (DA) neurons in PD. Therefore, investigating mitochondrial disorders plays a role in understanding the pathogenesis of PD and can be an important therapeutic target for this disease. This study discusses the effect of environmental, genetic and biological factors on mitochondrial dysfunction and also focuses on the mitochondrial molecular mechanisms underlying neurodegeneration, and its possible therapeutic targets in PD, including reactive oxygen species generation, calcium overload, inflammasome activation, apoptosis, mitophagy, mitochondrial biogenesis, and mitochondrial dynamics. Other potential therapeutic strategies such as mitochondrial transfer/transplantation, targeting microRNAs, using stem cells, photobiomodulation, diet, and exercise were also discussed in this review, which may provide valuable insights into clinical aspects. A better understanding of the roles of mitochondria in the pathophysiology of PD may provide a rationale for designing novel therapeutic interventions in our fight against PD.
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Affiliation(s)
- Sadegh Moradi Vastegani
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ava Nasrolahi
- Infectious Ophthalmologic Research Center, Imam Khomeini Hospital Clinical Research Development Unit, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Shahab Ghaderi
- Department of Neuroscience, School of Science and Advanced Technologies in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Rafie Belali
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Masome Rashno
- Asadabad School of Medical Sciences, Asadabad, Iran
- Student Research Committee, Asadabad School of Medical Sciences, Asadabad, Iran
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Esmaeil Khoshnam
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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16
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Mitochondrial DNA Polymorphism in HV1 and HV2 Regions and 12S rDNA in Perimenopausal Hypertensive Women. Biomedicines 2023; 11:biomedicines11030823. [PMID: 36979802 PMCID: PMC10044999 DOI: 10.3390/biomedicines11030823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/05/2023] [Accepted: 03/07/2023] [Indexed: 03/11/2023] Open
Abstract
Estrogens enhance cellular mitochondrial activity. The diminution of female hormones during menopause may have an effect on the mitochondrial genome and the expression of mitochondrial proteins. Hence, oxidative stress and the pro-inflammatory state contribute to the formation of systemic illnesses including arterial hypertension (AH). This study aimed to determine the types and frequency of mutations in the mitochondrial DNA (mtDNA) nucleotide sequence in the hypervariable regions 1 and 2 (HV1 and HV2) and the 12S RNA coding sequence of the D-loop in postmenopausal women with hypertension. In our study, 100 women were investigated, 53 of whom were postmenopausal and 47 of whom were premenopausal (53.9 ± 3.7 years vs. 47.7 ± 4.2 years, respectively). Of those studied, 35 premenopausal and 40 postmenopausal women were diagnosed with AH. A medical checkup with 24 h monitoring of blood pressure (RR) and heart rate was undertaken (HR). The polymorphism of the D-loop and 12S rDNA region of mtDNA was examined. Changes in the nucleotide sequence of mtDNA were observed in 23% of the group of 100 women. The changes were identified in 91.3% of HV1 and HV2 regions, 60.9% of HV1 segments, 47.5% of HV2 regions, and 43.5% of 12S rDNA regions. The frequency of nucleotide sequence alterations in mtDNA was substantially higher in postmenopausal women (34%) than in premenopausal women (10.6%), p = 0.016. A higher frequency of changes in HV1 + HV2 sections in postmenopausal women (30.2%) compared to the premenopausal group (10.6%) was detected, p = 0.011. Only postmenopausal women were found to have modifications to the HV2 segment and the 12S rDNA region. After menopause, polymorphism in the mtDNA region was substantially more frequent in women with arterial hypertension than before menopause (p = 0.030; 37.5% vs. 11.5%). Comparable findings were observed in the HV2 and HV1 regions of the AH group (35% vs. 11.5%), p = 0.015, in the HV1 segment (25% vs. 11.5%), p = 0.529, and in the HV2 segment, 12S rDNA (25% vs. 0%). More than 80% of all changes in nucleotide sequence were homoplasmic. The mtDNA polymorphisms of the nucleotide sequence in the HV1 and HV2 regions, the HV2 region alone, and the 12S RNA coding sequence were associated with estrogen deficiency and a more severe course of arterial hypertension, accompanied by symptoms of adrenergic stimulation.
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17
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Lu S, Dai Z, Cui Y, Kong DM. Recent Development of Advanced Fluorescent Molecular Probes for Organelle-Targeted Cell Imaging. BIOSENSORS 2023; 13:360. [PMID: 36979572 PMCID: PMC10046058 DOI: 10.3390/bios13030360] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/10/2023] [Accepted: 02/20/2023] [Indexed: 06/18/2023]
Abstract
Fluorescent molecular probes are very powerful tools that have been generally applied in cell imaging in the research fields of biology, pathology, pharmacology, biochemistry, and medical science. In the last couple of decades, numerous molecular probes endowed with high specificity to particular organelles have been designed to illustrate intracellular images in more detail at the subcellular level. Nowadays, the development of cell biology has enabled the investigation process to go deeply into cells, even at the molecular level. Therefore, probes that can sketch a particular organelle's location while responding to certain parameters to evaluate intracellular bioprocesses are under urgent demand. It is significant to understand the basic ideas of organelle properties, as well as the vital substances related to each unique organelle, for the design of probes with high specificity and efficiency. In this review, we summarize representative multifunctional fluorescent molecular probes developed in the last decade. We focus on probes that can specially target nuclei, mitochondria, endoplasmic reticulums, and lysosomes. In each section, we first briefly introduce the significance and properties of different organelles. We then discuss how probes are designed to make them highly organelle-specific. Finally, we also consider how probes are constructed to endow them with additional functions to recognize particular physical/chemical signals of targeted organelles. Moreover, a perspective on the challenges in future applications of highly specific molecular probes in cell imaging is also proposed. We hope that this review can provide researchers with additional conceptual information about developing probes for cell imaging, assisting scientists interested in molecular biology, cell biology, and biochemistry to accelerate their scientific studies.
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Affiliation(s)
- Sha Lu
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Centre for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Zhiqi Dai
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Centre for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Yunxi Cui
- College of Life Sciences, Nankai University, Tianjin 300071, China
| | - De-Ming Kong
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Centre for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, China
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18
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Dahal S, Siddiqua H, Sharma S, Babu RK, Rathore D, Sharma S, Raghavan SC. Unleashing a novel function of Endonuclease G in mitochondrial genome instability. eLife 2022; 11:e69916. [PMID: 36394256 PMCID: PMC9711528 DOI: 10.7554/elife.69916] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 11/16/2022] [Indexed: 11/18/2022] Open
Abstract
Having its genome makes the mitochondrion a unique and semiautonomous organelle within cells. Mammalian mitochondrial DNA (mtDNA) is a double-stranded closed circular molecule of about 16 kb coding for 37 genes. Mutations, including deletions in the mitochondrial genome, can culminate in different human diseases. Mapping the deletion junctions suggests that the breakpoints are generally seen at hotspots. '9 bp deletion' (8271-8281), seen in the intergenic region of cytochrome c oxidase II/tRNALys, is the most common mitochondrial deletion. While it is associated with several diseases like myopathy, dystonia, and hepatocellular carcinoma, it has also been used as an evolutionary marker. However, the mechanism responsible for its fragility is unclear. In the current study, we show that Endonuclease G, a mitochondrial nuclease responsible for nonspecific cleavage of nuclear DNA during apoptosis, can induce breaks at sequences associated with '9 bp deletion' when it is present on a plasmid or in the mitochondrial genome. Through a series of in vitro and intracellular studies, we show that Endonuclease G binds to G-quadruplex structures formed at the hotspot and induces DNA breaks. Therefore, we uncover a new role for Endonuclease G in generating mtDNA deletions, which depends on the formation of G4 DNA within the mitochondrial genome. In summary, we identify a novel property of Endonuclease G, besides its role in apoptosis and the recently described 'elimination of paternal mitochondria during fertilisation.
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Affiliation(s)
- Sumedha Dahal
- Department of Biochemistry, Indian Institute of Science BangaloreBangaloreIndia
| | - Humaira Siddiqua
- Department of Biochemistry, Indian Institute of Science BangaloreBangaloreIndia
| | - Shivangi Sharma
- Department of Biochemistry, Indian Institute of Science BangaloreBangaloreIndia
| | - Ravi K Babu
- Department of Biochemistry, Indian Institute of Science BangaloreBangaloreIndia
| | - Diksha Rathore
- Department of Biochemistry, Indian Institute of Science BangaloreBangaloreIndia
| | - Sheetal Sharma
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and ResearchChandigarhIndia
| | - Sathees C Raghavan
- Department of Biochemistry, Indian Institute of Science BangaloreBangaloreIndia
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19
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Chiaratti MR, Chinnery PF. Modulating mitochondrial DNA mutations: factors shaping heteroplasmy in the germ line and somatic cells. Pharmacol Res 2022; 185:106466. [PMID: 36174964 DOI: 10.1016/j.phrs.2022.106466] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/21/2022] [Accepted: 09/23/2022] [Indexed: 11/30/2022]
Abstract
Until recently it was thought that most humans only harbor one type of mitochondrial DNA (mtDNA), however, deep sequencing and single-cell analysis has shown the converse - that mixed populations of mtDNA (heteroplasmy) are the norm. This is important because heteroplasmy levels can change dramatically during transmission in the female germ line, leading to high levels causing severe mitochondrial diseases. There is also emerging evidence that low level mtDNA mutations contribute to common late onset diseases such as neurodegenerative disorders and cardiometabolic diseases because the inherited mutation levels can change within developing organs and non-dividing cells over time. Initial predictions suggested that the segregation of mtDNA heteroplasmy was largely stochastic, with an equal tendency for levels to increase or decrease. However, transgenic animal work and single-cell analysis have shown this not to be the case during germ-line transmission and in somatic tissues during life. Mutation levels in specific mtDNA regions can increase or decrease in different contexts and the underlying molecular mechanisms are starting to be unraveled. In this review we provide a synthesis of recent literature on the mechanisms of selection for and against mtDNA variants. We identify the most pertinent gaps in our understanding and suggest ways these could be addressed using state of the art techniques.
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Affiliation(s)
- Marcos R Chiaratti
- Departamento de Genética e Evolução, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, São Carlos, Brazil.
| | - Patrick F Chinnery
- Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
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20
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Chen Y, Yang F, Chu Y, Yun Z, Yan Y, Jin J. Mitochondrial transplantation: opportunities and challenges in the treatment of obesity, diabetes, and nonalcoholic fatty liver disease. Lab Invest 2022; 20:483. [PMID: 36273156 PMCID: PMC9588235 DOI: 10.1186/s12967-022-03693-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 10/06/2022] [Indexed: 11/23/2022]
Abstract
Metabolic diseases, including obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD), are rising in both incidence and prevalence and remain a major global health and socioeconomic burden in the twenty-first century. Despite an increasing understanding of these diseases, the lack of effective treatments remains an ongoing challenge. Mitochondria are key players in intracellular energy production, calcium homeostasis, signaling, and apoptosis. Emerging evidence shows that mitochondrial dysfunction participates in the pathogeneses of metabolic diseases. Exogenous supplementation with healthy mitochondria is emerging as a promising therapeutic approach to treating these diseases. This article reviews recent advances in the use of mitochondrial transplantation therapy (MRT) in such treatment.
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Affiliation(s)
- Yifei Chen
- Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China.,School of Medicine, Jiangsu University, ZhenjiangJiangsu Province, 212013, China
| | - Fuji Yang
- Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China.,School of Medicine, Jiangsu University, ZhenjiangJiangsu Province, 212013, China
| | - Ying Chu
- Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China.,Central Laboratory, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China
| | - Zhihua Yun
- Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China
| | - Yongmin Yan
- Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China. .,Central Laboratory, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China.
| | - Jianhua Jin
- Department of Oncology, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, Jiangsu Province, China.
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21
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Tostes K, dos Santos AC, Alves LO, Bechara LRG, Marascalchi R, Macabelli CH, Grejo MP, Festuccia WT, Gottlieb RA, Ferreira JCB, Chiaratti MR. Autophagy deficiency abolishes liver mitochondrial DNA segregation. Autophagy 2022; 18:2397-2408. [PMID: 35220898 PMCID: PMC9542960 DOI: 10.1080/15548627.2022.2038501] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Mutations in the mitochondrial genome (mtDNA) are ubiquitous in humans and can lead to a broad spectrum of disorders. However, due to the presence of multiple mtDNA molecules in the cell, co-existence of mutant and wild-type mtDNAs (termed heteroplasmy) can mask disease phenotype unless a threshold of mutant molecules is reached. Importantly, the mutant mtDNA level can change across lifespan as mtDNA segregates in an allele- and cell-specific fashion, potentially leading to disease. Segregation of mtDNA is mainly evident in hepatic cells, resulting in an age-dependent increase of mtDNA variants, including non-synonymous potentially deleterious mutations. Here we modeled mtDNA segregation using a well-established heteroplasmic mouse line with mtDNA of NZB/BINJ and C57BL/6N origin on a C57BL/6N nuclear background. This mouse line showed a pronounced age-dependent NZB mtDNA accumulation in the liver, thus leading to enhanced respiration capacity per mtDNA molecule. Remarkably, liver-specific atg7 (autophagy related 7) knockout abolished NZB mtDNA accumulat ion, resulting in close-to-neutral mtDNA segregation through development into adulthood. prkn (parkin RBR E3 ubiquitin protein ligase) knockout also partially prevented NZB mtDNA accumulation in the liver, but to a lesser extent. Hence, we propose that age-related liver mtDNA segregation is a consequence of macroautophagic clearance of the less-fit mtDNA. Considering that NZB/BINJ and C57BL/6N mtDNAs have a level of divergence comparable to that between human Eurasian and African mtDNAs, these findings have potential implications for humans, including the safe use of mitochondrial replacement therapy.Abbreviations: Apob: apolipoprotein B; Atg1: autophagy-related 1; Atg7: autophagy related 7; Atp5a1: ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1; BL6: C57BL/6N mouse strain; BNIP3: BCL2/adenovirus E1B interacting protein 3; FCCP: carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; MAP1LC3A: microtubule-associated protein 1 light chain 3 alpha; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; mt-Atp8: mitochondrially encoded ATP synthase 8; MT-CO1: mitochondrially encoded cytochrome c oxidase I; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mt-Co3: mitochondrially encoded cytochrome c oxidase III; mt-Cytb: mitochondrially encoded cytochrome b; mtDNA: mitochondrial DNA; MUL1: mitochondrial ubiquitin ligase activator of NFKB 1; nDNA: nuclear DNA; Ndufa9: NADH:ubiquinone oxireductase subunit A9; NDUFB8: NADH:ubiquinone oxireductase subunit B8; Nnt: nicotinamide nucleotide transhydrogenase; NZB: NZB/BINJ mouse strain; OXPHOS: oxidative phosphorylation; PINK1: PTEN induced putative kinase 1; Polg2: polymerase (DNA directed), gamma 2, accessory subunit; Ppara: peroxisome proliferator activated receptor alpha; Ppia: peptidylprolyl isomerase A; Prkn: parkin RBR E3 ubiquitin protein ligase; P10: post-natal day 10; P21: post-natal day 21; P100: post-natal day 100; qPCR: quantitative polymerase chain reaction; Rpl19: ribosomal protein L19; Rps18: ribosomal protein S18; SD: standard deviation; SEM: standard error of the mean; SDHB: succinate dehydrogenase complex, subunit B, iron sulfur (Ip); SQSTM1: sequestosome 1; Ssbp1: single-stranded DNA binding protein 1; TFAM: transcription factor A, mitochondrial; Tfb1m: transcription factor B1, mitochondrial; Tfb2m: transcription factor B2, mitochondrial; TOMM20: translocase of outer mitochondrial membrane 20; UQCRC2: ubiquinol cytochrome c reductase core protein 2; WT: wild-type.
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Affiliation(s)
- Katiane Tostes
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil
| | - Angélica C. dos Santos
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil
| | - Lindomar O. Alves
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil
| | - Luiz R. G. Bechara
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Rachel Marascalchi
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil
| | - Carolina H. Macabelli
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil
| | - Mateus P. Grejo
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil
| | - William T. Festuccia
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Roberta A. Gottlieb
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Julio C. B. Ferreira
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil,Department of Chemical and Systems Biology, Stanford University School of Medicine, CA, USA
| | - Marcos R. Chiaratti
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil,CONTACT Marcos R. Chiaratti Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos13565-905, Brazil
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22
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Abstract
Unknown processes promote the accumulation of mitochondrial DNA (mtDNA) mutations during aging. Accumulation of defective mitochondrial genomes is thought to promote the progression of heteroplasmic mitochondrial diseases and degenerative changes with natural aging. We used a heteroplasmic Drosophila model to test 1) whether purifying selection acts to limit the abundance of deleterious mutations during development and aging, 2) whether quality control pathways contribute to purifying selection, 3) whether activation of quality control can mitigate accumulation of deleterious mutations, and 4) whether improved quality control improves health span. We show that purifying selection operates during development and growth but is ineffective during aging. Genetic manipulations suggest that a quality control process known to enforce purifying selection during oogenesis also suppresses accumulation of a deleterious mutation during growth and development. Flies with nuclear genotypes that enhance purifying selection sustained higher genome quality, retained more vigorous climbing activity, and lost fewer dopaminergic neurons. A pharmacological agent thought to enhance quality control produced similar benefits. Importantly, similar pharmacological treatment of aged mice reversed age-associated accumulation of a deleterious mtDNA mutation. Our findings reveal dynamic maintenance of mitochondrial genome fitness and reduction in the effectiveness of purifying selection during life. Importantly, we describe interventions that mitigate and even reverse age-associated genome degeneration in flies and in mice. Furthermore, mitigation of genome degeneration improved well-being in a Drosophila model of heteroplasmic mitochondrial disease.
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23
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Lambert-Smith IA, Saunders DN, Yerbury JJ. Progress in biophysics and molecular biology proteostasis impairment and ALS. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2022; 174:3-27. [PMID: 35716729 DOI: 10.1016/j.pbiomolbio.2022.06.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 05/19/2022] [Accepted: 06/09/2022] [Indexed: 12/11/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disease that results from the loss of both upper and lower motor neurons. It is the most common motor neuron disease and currently has no effective treatment. There is mounting evidence to suggest that disturbances in proteostasis play a significant role in ALS pathogenesis. Proteostasis is the maintenance of the proteome at the right level, conformation and location to allow a cell to perform its intended function. In this review, we present a thorough synthesis of the literature that provides evidence that genetic mutations associated with ALS cause imbalance to a proteome that is vulnerable to such pressure due to its metastable nature. We propose that the mechanism underlying motor neuron death caused by defects in mRNA metabolism and protein degradation pathways converges on proteostasis dysfunction. We propose that the proteostasis network may provide an effective target for therapeutic development in ALS.
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Affiliation(s)
- Isabella A Lambert-Smith
- Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia; Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia
| | - Darren N Saunders
- Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia
| | - Justin J Yerbury
- Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia; Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia.
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24
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Roy A, Kandettu A, Ray S, Chakrabarty S. Mitochondrial DNA replication and repair defects: Clinical phenotypes and therapeutic interventions. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2022; 1863:148554. [PMID: 35341749 DOI: 10.1016/j.bbabio.2022.148554] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 03/06/2022] [Accepted: 03/16/2022] [Indexed: 12/15/2022]
Abstract
Mitochondria is a unique cellular organelle involved in multiple cellular processes and is critical for maintaining cellular homeostasis. This semi-autonomous organelle contains its circular genome - mtDNA (mitochondrial DNA), that undergoes continuous cycles of replication and repair to maintain the mitochondrial genome integrity. The majority of the mitochondrial genes, including mitochondrial replisome and repair genes, are nuclear-encoded. Although the repair machinery of mitochondria is quite efficient, the mitochondrial genome is highly susceptible to oxidative damage and other types of exogenous and endogenous agent-induced DNA damage, due to the absence of protective histones and their proximity to the main ROS production sites. Mutations in replication and repair genes of mitochondria can result in mtDNA depletion and deletions subsequently leading to mitochondrial genome instability. The combined action of mutations and deletions can result in compromised mitochondrial genome maintenance and lead to various mitochondrial disorders. Here, we review the mechanism of mitochondrial DNA replication and repair process, key proteins involved, and their altered function in mitochondrial disorders. The focus of this review will be on the key genes of mitochondrial DNA replication and repair machinery and the clinical phenotypes associated with mutations in these genes.
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Affiliation(s)
- Abhipsa Roy
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Amoolya Kandettu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Swagat Ray
- Department of Life Sciences, School of Life and Environmental Sciences, University of Lincoln, Lincoln LN6 7TS, United Kingdom
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
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25
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Lang M, Grünewald A, Pramstaller PP, Hicks AA, Pichler I. A genome on shaky ground: exploring the impact of mitochondrial DNA integrity on Parkinson's disease by highlighting the use of cybrid models. Cell Mol Life Sci 2022; 79:283. [PMID: 35513611 PMCID: PMC9072496 DOI: 10.1007/s00018-022-04304-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/01/2022] [Accepted: 04/12/2022] [Indexed: 11/29/2022]
Abstract
Mitochondria play important roles in the regulation of key cellular processes, including energy metabolism, oxidative stress response, and signaling towards cell death or survival, and are distinguished by carrying their own genome (mtDNA). Mitochondrial dysfunction has emerged as a prominent cellular mechanism involved in neurodegeneration, including Parkinson’s disease (PD), a neurodegenerative movement disorder, characterized by progressive loss of dopaminergic neurons and the occurrence of proteinaceous Lewy body inclusions. The contribution of mtDNA variants to PD pathogenesis has long been debated and is still not clearly answered. Cytoplasmic hybrid (cybrid) cell models provided evidence for a contribution of mtDNA variants to the PD phenotype. However, conclusive evidence of mtDNA mutations as genetic cause of PD is still lacking. Several models have shown a role of somatic, rather than inherited mtDNA variants in the impairment of mitochondrial function and neurodegeneration. Accordingly, several nuclear genes driving inherited forms of PD are linked to mtDNA quality control mechanisms, and idiopathic as well as familial PD tissues present increased mtDNA damage. In this review, we highlight the use of cybrids in this PD research field and summarize various aspects of how and to what extent mtDNA variants may contribute to the etiology of PD.
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Affiliation(s)
- Martin Lang
- Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy.
| | - Anne Grünewald
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362, Esch-sur-Alzette, Luxembourg
| | - Peter P Pramstaller
- Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy.,Department of Neurology, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Andrew A Hicks
- Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy
| | - Irene Pichler
- Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy.
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26
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Hyun DH, Lee J. A New Insight into an Alternative Therapeutic Approach to Restore Redox Homeostasis and Functional Mitochondria in Neurodegenerative Diseases. Antioxidants (Basel) 2021; 11:antiox11010007. [PMID: 35052511 PMCID: PMC8772965 DOI: 10.3390/antiox11010007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 11/16/2022] Open
Abstract
Neurodegenerative diseases are accompanied by oxidative stress and mitochondrial dysfunction, leading to a progressive loss of neuronal cells, formation of protein aggregates, and a decrease in cognitive or motor functions. Mitochondrial dysfunction occurs at the early stage of neurodegenerative diseases. Protein aggregates containing oxidatively damaged biomolecules and other misfolded proteins and neuroinflammation have been identified in animal models and patients with neurodegenerative diseases. A variety of neurodegenerative diseases commonly exhibits decreased activity of antioxidant enzymes, lower amounts of antioxidants, and altered cellular signalling. Although several molecules have been approved clinically, there is no known cure for neurodegenerative diseases, though some drugs are focused on improving mitochondrial function. Mitochondrial dysfunction is caused by oxidative damage and impaired cellular signalling, including that of peroxisome proliferator-activated receptor gamma coactivator 1α. Mitochondrial function can also be modulated by mitochondrial biogenesis and the mitochondrial fusion/fission cycle. Mitochondrial biogenesis is regulated mainly by sirtuin 1, NAD+, AMP-activated protein kinase, mammalian target of rapamycin, and peroxisome proliferator-activated receptor γ. Altered mitochondrial dynamics, such as increased fission proteins and decreased fusion products, are shown in neurodegenerative diseases. Due to the restrictions of a target-based approach, a phenotype-based approach has been performed to find novel proteins or pathways. Alternatively, plasma membrane redox enzymes improve mitochondrial function without the further production of reactive oxygen species. In addition, inducers of antioxidant response elements can be useful to induce a series of detoxifying enzymes. Thus, redox homeostasis and metabolic regulation can be important therapeutic targets for delaying the progression of neurodegenerative diseases.
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27
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Habbane M, Montoya J, Rhouda T, Sbaoui Y, Radallah D, Emperador S. Human Mitochondrial DNA: Particularities and Diseases. Biomedicines 2021; 9:biomedicines9101364. [PMID: 34680481 PMCID: PMC8533111 DOI: 10.3390/biomedicines9101364] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/21/2021] [Accepted: 09/23/2021] [Indexed: 11/25/2022] Open
Abstract
Mitochondria are the cell’s power site, transforming energy into a form that the cell can employ for necessary metabolic reactions. These organelles present their own DNA. Although it codes for a small number of genes, mutations in mtDNA are common. Molecular genetics diagnosis allows the analysis of DNA in several areas such as infectiology, oncology, human genetics and personalized medicine. Knowing that the mitochondrial DNA is subject to several mutations which have a direct impact on the metabolism of the mitochondrion leading to many diseases, it is therefore necessary to detect these mutations in the patients involved. To date numerous mitochondrial mutations have been described in humans, permitting confirmation of clinical diagnosis, in addition to a better management of the patients. Therefore, different techniques are employed to study the presence or absence of mitochondrial mutations. However, new mutations are discovered, and to determine if they are the cause of disease, different functional mitochondrial studies are undertaken using transmitochondrial cybrid cells that are constructed by fusion of platelets of the patient that presents the mutation, with rho osteosarcoma cell line. Moreover, the contribution of next generation sequencing allows sequencing of the entire human genome within a single day and should be considered in the diagnosis of mitochondrial mutations.
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Affiliation(s)
- Mouna Habbane
- Laboratoire Biologie et Santé, Faculté des sciences Ben M’Sick, Hassan II University of Casablanca, Sidi Othman, Casablanca 20670, Morocco; (T.R.); (D.R.)
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; (J.M.); (S.E.)
- Correspondence: ; Tel.: +212-701-105-108
| | - Julio Montoya
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; (J.M.); (S.E.)
- Instituto de Investigación Sanitaria (IIS) de Aragón, Av. San Juan Bosco, 13, 50009 Zaragoza, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain
| | - Taha Rhouda
- Laboratoire Biologie et Santé, Faculté des sciences Ben M’Sick, Hassan II University of Casablanca, Sidi Othman, Casablanca 20670, Morocco; (T.R.); (D.R.)
| | - Yousra Sbaoui
- Département de Biologie, Faculté des Sciences Ain Chock, Hassan II University of Casablanca, Casablanca 20000, Morocco;
| | - Driss Radallah
- Laboratoire Biologie et Santé, Faculté des sciences Ben M’Sick, Hassan II University of Casablanca, Sidi Othman, Casablanca 20670, Morocco; (T.R.); (D.R.)
| | - Sonia Emperador
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; (J.M.); (S.E.)
- Instituto de Investigación Sanitaria (IIS) de Aragón, Av. San Juan Bosco, 13, 50009 Zaragoza, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain
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28
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Weidling IW, Wilkins HM, Koppel SJ, Hutfles L, Wang X, Kalani A, Menta BW, Ryan B, Perez-Ortiz J, Gamblin TC, Swerdlow RH. Mitochondrial DNA Manipulations Affect Tau Oligomerization. J Alzheimers Dis 2021; 77:149-163. [PMID: 32804126 PMCID: PMC7962146 DOI: 10.3233/jad-200286] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Mitochondrial dysfunction and tau aggregation occur in Alzheimer's disease (AD), and exposing cells or rodents to mitochondrial toxins alters their tau. OBJECTIVE To further explore how mitochondria influence tau, we measured tau oligomer levels in human neuronal SH-SY5Y cells with different mitochondrial DNA (mtDNA) manipulations. METHODS Specifically, we analyzed cells undergoing ethidium bromide-induced acute mtDNA depletion, ρ0 cells with chronic mtDNA depletion, and cytoplasmic hybrid (cybrid) cell lines containing mtDNA from AD subjects. RESULTS We found cytochrome oxidase activity was particularly sensitive to acute mtDNA depletion, evidence of metabolic re-programming in the ρ0 cells, and a relatively reduced mtDNA content in cybrids generated through AD subject mitochondrial transfer. In each case tau oligomer levels increased, and acutely depleted and AD cybrid cells also showed a monomer to oligomer shift. CONCLUSION We conclude a cell's mtDNA affects tau oligomerization. Overlapping tau changes across three mtDNA-manipulated models establishes the reproducibility of the phenomenon, and its presence in AD cybrids supports its AD-relevance.
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Affiliation(s)
- Ian W Weidling
- University of Kansas Alzheimer's Disease Center; the University of Kansas Medical Center, Kansas City, KS, USA.,Departments of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.,Molecular and Integrative Physiology, and University of Kansas Medical Center, Kansas City, KS, USA
| | - Heather M Wilkins
- University of Kansas Alzheimer's Disease Center; the University of Kansas Medical Center, Kansas City, KS, USA.,Departments of Neurology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Scott J Koppel
- University of Kansas Alzheimer's Disease Center; the University of Kansas Medical Center, Kansas City, KS, USA.,Departments of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.,Molecular and Integrative Physiology, and University of Kansas Medical Center, Kansas City, KS, USA
| | - Lewis Hutfles
- University of Kansas Alzheimer's Disease Center; the University of Kansas Medical Center, Kansas City, KS, USA
| | - Xiaowan Wang
- University of Kansas Alzheimer's Disease Center; the University of Kansas Medical Center, Kansas City, KS, USA.,Departments of Neurology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Anuradha Kalani
- University of Kansas Alzheimer's Disease Center; the University of Kansas Medical Center, Kansas City, KS, USA.,Departments of Neurology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Blaise W Menta
- University of Kansas Alzheimer's Disease Center; the University of Kansas Medical Center, Kansas City, KS, USA.,Departments of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.,Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Benjamin Ryan
- University of Kansas Alzheimer's Disease Center; the University of Kansas Medical Center, Kansas City, KS, USA.,Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Judit Perez-Ortiz
- University of Kansas Alzheimer's Disease Center; the University of Kansas Medical Center, Kansas City, KS, USA.,Departments of Neurology, University of Kansas Medical Center, Kansas City, KS, USA
| | - T Chris Gamblin
- Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
| | - Russell H Swerdlow
- University of Kansas Alzheimer's Disease Center; the University of Kansas Medical Center, Kansas City, KS, USA.,Departments of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.,Molecular and Integrative Physiology, and University of Kansas Medical Center, Kansas City, KS, USA.,Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA
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29
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Wei W, Gaffney DJ, Chinnery PF. Cell reprogramming shapes the mitochondrial DNA landscape. Nat Commun 2021; 12:5241. [PMID: 34475388 PMCID: PMC8413449 DOI: 10.1038/s41467-021-25482-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 08/14/2021] [Indexed: 12/25/2022] Open
Abstract
Individual induced pluripotent stem cells (iPSCs) show considerable phenotypic heterogeneity, but the reasons for this are not fully understood. Comprehensively analysing the mitochondrial genome (mtDNA) in 146 iPSC and fibroblast lines from 151 donors, we show that most age-related fibroblast mtDNA mutations are lost during reprogramming. However, iPSC-specific mutations are seen in 76.6% (108/141) of iPSC lines at a mutation rate of 8.62 × 10-5/base pair. The mutations observed in iPSC lines affect a higher proportion of mtDNA molecules, favouring non-synonymous protein-coding and tRNA variants, including known disease-causing mutations. Analysing 11,538 single cells shows stable heteroplasmy in sub-clones derived from the original donor during differentiation, with mtDNA variants influencing the expression of key genes involved in mitochondrial metabolism and epidermal cell differentiation. Thus, the dynamic mtDNA landscape contributes to the heterogeneity of human iPSCs and should be considered when using reprogrammed cells experimentally or as a therapy.
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Affiliation(s)
- Wei Wei
- Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK
- Medical Research Council Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Daniel J Gaffney
- Human Induced Pluripotent Stem Cell Initiative, Wellcome Genome Campus, Hinxton, UK
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Patrick F Chinnery
- Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK.
- Medical Research Council Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
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30
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Roca-Bayerri C, Robertson F, Pyle A, Hudson G, Payne BAI. Mitochondrial DNA Damage and Brain Aging in Human Immunodeficiency Virus. Clin Infect Dis 2021; 73:e466-e473. [PMID: 32722761 PMCID: PMC8282328 DOI: 10.1093/cid/ciaa984] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 07/14/2020] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Neurocognitive impairment (NCI) remains common in people living with human immunodeficiency virus (PLWH), despite suppressive antiretroviral therapy (ART), but the reasons remain incompletely understood. Mitochondrial dysfunction is a hallmark of aging and of neurodegenerative diseases. We hypothesized that human immunodeficiency virus (HIV) or ART may lead to mitochondrial abnormalities in the brain, thus contributing to NCI. METHODS We studied postmortem frozen brain samples from 52 PLWH and 40 HIV-negative controls. Cellular mitochondrial DNA (mtDNA) content and levels of large-scale mtDNA deletions were measured by real-time polymerase chain reaction. Heteroplasmic mtDNA point mutations were quantified by deep sequencing (Illumina). Neurocognitive data were taken within 48 months antemortem. RESULTS We observed a decrease in mtDNA content, an increase in the mtDNA "common deletion," and an increase in mtDNA point mutations with age (all P < .05). Each of these changes was exacerbated in HIV-positive cases compared with HIV-negative controls (all P < .05). ART exposures, including nucleoside analogue reverse transcriptase inhibitors, were not associated with changes in mtDNA. The number of mtDNA point mutations was associated with low CD4/CD8 ratio (P = .04) and with NCI (global T-score, P = .007). CONCLUSIONS In people with predominantly advanced HIV infection, there is exacerbation of age-associated mtDNA damage. This change is driven by HIV per se rather than by ART toxicity and may contribute to NCI. These data suggest that mitochondrial dysfunction may be a mediator of adverse aging phenotypes in PLWH.
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Affiliation(s)
- Carla Roca-Bayerri
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom
| | - Fiona Robertson
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom
| | - Angela Pyle
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom
| | - Gavin Hudson
- Wellcome Centre for Mitochondrial Research, Biosciences Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom
| | - Brendan A I Payne
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom
- Department of Infection and Tropical Medicine, Newcastle-upon-Tyne Hospitals, Newcastle-upon-Tyne, United Kingdom
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31
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Mitostasis, Calcium and Free Radicals in Health, Aging and Neurodegeneration. Biomolecules 2021; 11:biom11071012. [PMID: 34356637 PMCID: PMC8301949 DOI: 10.3390/biom11071012] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 12/18/2022] Open
Abstract
Mitochondria play key roles in ATP supply, calcium homeostasis, redox balance control and apoptosis, which in neurons are fundamental for neurotransmission and to allow synaptic plasticity. Their functional integrity is maintained by mitostasis, a process that involves mitochondrial transport, anchoring, fusion and fission processes regulated by different signaling pathways but mainly by the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α also favors Ca2+ homeostasis, reduces oxidative stress, modulates inflammatory processes and mobilizes mitochondria to where they are needed. To achieve their functions, mitochondria are tightly connected to the endoplasmic reticulum (ER) through specialized structures of the ER termed mitochondria-associated membranes (MAMs), which facilitate the communication between these two organelles mainly to aim Ca2+ buffering. Alterations in mitochondrial activity enhance reactive oxygen species (ROS) production, disturbing the physiological metabolism and causing cell damage. Furthermore, cytosolic Ca2+ overload results in an increase in mitochondrial Ca2+, resulting in mitochondrial dysfunction and the induction of mitochondrial permeability transition pore (mPTP) opening, leading to mitochondrial swelling and cell death through apoptosis as demonstrated in several neuropathologies. In summary, mitochondrial homeostasis is critical to maintain neuronal function; in fact, their regulation aims to improve neuronal viability and to protect against aging and neurodegenerative diseases.
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32
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Dahal S, Siddiqua H, Katapadi VK, Iyer D, Raghavan SC. Characterization of G4 DNA formation in mitochondrial DNA and their potential role in mitochondrial genome instability. FEBS J 2021; 289:163-182. [PMID: 34228888 DOI: 10.1111/febs.16113] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/29/2021] [Accepted: 07/06/2021] [Indexed: 12/16/2022]
Abstract
Mitochondria possess their own genome which can be replicated independently of nuclear DNA. Mitochondria being the powerhouse of the cell produce reactive oxygen species, due to which the mitochondrial genome is frequently exposed to oxidative damage. Previous studies have demonstrated an association of mitochondrial deletions to aging and human disorders. Many of these deletions were present adjacent to non-B DNA structures. Thus, we investigate noncanonical structures associated with instability in mitochondrial genome. In silico studies revealed the presence of > 100 G-quadruplex motifs (of which 5 have the potential to form 3-plate G4 DNA), 23 inverted repeats, and 3 mirror repeats in the mitochondrial DNA (mtDNA). Further analysis revealed that among the deletion breakpoints from patients with mitochondrial disorders, majority are located at G4 DNA motifs. Interestingly, ~ 50% of the deletions were at base-pair positions 8271-8281, ~ 35% were due to deletion at 12362-12384, and ~ 12% due to deletion at 15516-15545. Formation of 3-plate G-quadruplex DNA structures at mitochondrial fragile regions was characterized using electromobility shift assay, circular dichroism (CD), and Taq polymerase stop assay. All 5 regions could fold into both intramolecular and intermolecular G-quadruplex structures in a KCl-dependent manner. G4 DNA formation was in parallel orientation, which was abolished in the presence of LiCl. The formation of G4 DNA affected both replication and transcription. Finally, immunolocalization of BG4 with MitoTracker confirmed the formation of G-quadruplex in mitochondrial genome. Thus, we characterize the formation of 5 different G-quadruplex structures in human mitochondrial region, which may contribute toward formation of mitochondrial deletions.
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Affiliation(s)
- Sumedha Dahal
- Department of Biochemistry, Indian Institute of Science, Bangalore, India
| | - Humaira Siddiqua
- Department of Biochemistry, Indian Institute of Science, Bangalore, India
| | - Vijeth K Katapadi
- Department of Biochemistry, Indian Institute of Science, Bangalore, India
| | - Divyaanka Iyer
- Department of Biochemistry, Indian Institute of Science, Bangalore, India
| | - Sathees C Raghavan
- Department of Biochemistry, Indian Institute of Science, Bangalore, India
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33
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Abstract
SUMMARY The genetic basis of youthfulness is poorly understood. The aging of skin depends on both intrinsic factors and extrinsic factors. Intrinsic factors include personal genetics, and extrinsic factors include environmental exposure to solar radiation and pollution. We recently reported the critical role of the mitochondria in skin aging phenotypes: wrinkle formation, hair graying, hair loss, and uneven skin pigmentation. This article focuses on molecular mechanisms, specifically mitochondrial mechanisms underlying skin aging. This contribution describes the development of an mitochondrial DNA depleter-repleter mouse model and its usefulness in developing strategies and identifying potential agents that can either prevent, slow, or mitigate skin aging, lentigines, and hair loss. The ongoing research efforts include the transplantation of young mitochondria to rejuvenate aging skin and hair to provide youthfulness in humans.
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Affiliation(s)
- Keshav K Singh
- From the Integrative Center for Aging Research, O'Neal Comprehensive Cancer Center, Department of Genetics, UAB School of Medicine, University of Alabama at Birmingham
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34
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Morshneva A, Kozyulina P, Vashukova E, Tarasenko O, Dvoynova N, Chentsova A, Talantova O, Koroteev A, Ivanov D, Serebryakova E, Ivashchenko T, Sukhomyasova A, Maksimova N, Bespalova O, Kogan I, Baranov V, Glotov A. Pilot Screening of Cell-Free mtDNA in NIPT: Quality Control, Variant Calling, and Haplogroup Determination. Genes (Basel) 2021; 12:743. [PMID: 34069212 PMCID: PMC8156457 DOI: 10.3390/genes12050743] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/07/2021] [Accepted: 05/11/2021] [Indexed: 12/31/2022] Open
Abstract
Clinical tests based on whole-genome sequencing are generally focused on a single task approach, testing one or several parameters, although whole-genome sequencing (WGS) provides us with large data sets that can be used for many supportive analyses. In spite of low genome coverage, data of WGS-based non-invasive prenatal testing (NIPT) contain fully sequenced mitochondrial DNA (mtDNA). This mtDNA can be used for variant calling, ancestry analysis, population studies and other approaches that extend NIPT functionality. In this study, we analyse mtDNA pool from 645 cell-free DNA (cfDNA) samples of pregnant women from different regions of Russia, explore the effects of transportation and storing conditions on mtDNA content, analyse effects, frequency and location of mitochondrial variants called from samples and perform haplogroup analysis, revealing the most common mitochondrial superclades. We have shown that, despite the relatively low sequencing depth of unamplified mtDNA from cfDNA samples, the mtDNA analysis in these samples is still an informative instrument suitable for research and screening purposes.
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Affiliation(s)
- Alisa Morshneva
- D.O. Ott Research Institute for Obstetrics, Gynaecology and Reproductology, Mendeleevskaya Line 3, 199034 St. Petersburg, Russia; (P.K.); (E.V.); (O.T.); (O.T.); (E.S.); (T.I.); (O.B.); (I.K.); (V.B.); (A.G.)
- Ltd NIPT, Bolshoi V.O. 90, Building 2 lit. 3, 199106 St. Petersburg, Russia; (N.D.); (A.C.)
| | - Polina Kozyulina
- D.O. Ott Research Institute for Obstetrics, Gynaecology and Reproductology, Mendeleevskaya Line 3, 199034 St. Petersburg, Russia; (P.K.); (E.V.); (O.T.); (O.T.); (E.S.); (T.I.); (O.B.); (I.K.); (V.B.); (A.G.)
- Ltd NIPT, Bolshoi V.O. 90, Building 2 lit. 3, 199106 St. Petersburg, Russia; (N.D.); (A.C.)
| | - Elena Vashukova
- D.O. Ott Research Institute for Obstetrics, Gynaecology and Reproductology, Mendeleevskaya Line 3, 199034 St. Petersburg, Russia; (P.K.); (E.V.); (O.T.); (O.T.); (E.S.); (T.I.); (O.B.); (I.K.); (V.B.); (A.G.)
- Ltd NIPT, Bolshoi V.O. 90, Building 2 lit. 3, 199106 St. Petersburg, Russia; (N.D.); (A.C.)
| | - Olga Tarasenko
- D.O. Ott Research Institute for Obstetrics, Gynaecology and Reproductology, Mendeleevskaya Line 3, 199034 St. Petersburg, Russia; (P.K.); (E.V.); (O.T.); (O.T.); (E.S.); (T.I.); (O.B.); (I.K.); (V.B.); (A.G.)
- Ltd NIPT, Bolshoi V.O. 90, Building 2 lit. 3, 199106 St. Petersburg, Russia; (N.D.); (A.C.)
| | - Natalia Dvoynova
- Ltd NIPT, Bolshoi V.O. 90, Building 2 lit. 3, 199106 St. Petersburg, Russia; (N.D.); (A.C.)
| | - Anastasia Chentsova
- Ltd NIPT, Bolshoi V.O. 90, Building 2 lit. 3, 199106 St. Petersburg, Russia; (N.D.); (A.C.)
| | - Olga Talantova
- D.O. Ott Research Institute for Obstetrics, Gynaecology and Reproductology, Mendeleevskaya Line 3, 199034 St. Petersburg, Russia; (P.K.); (E.V.); (O.T.); (O.T.); (E.S.); (T.I.); (O.B.); (I.K.); (V.B.); (A.G.)
| | - Alexander Koroteev
- St. Petersburg State Pediatric Medical University, 2 Litovskaya Street, 194100 St. Petersburg, Russia; (A.K.); (D.I.)
- Center for Medical Genetics, Tobolskaya ul. 5, 194044 St. Petersburg, Russia
| | - Dmitrii Ivanov
- St. Petersburg State Pediatric Medical University, 2 Litovskaya Street, 194100 St. Petersburg, Russia; (A.K.); (D.I.)
| | - Elena Serebryakova
- D.O. Ott Research Institute for Obstetrics, Gynaecology and Reproductology, Mendeleevskaya Line 3, 199034 St. Petersburg, Russia; (P.K.); (E.V.); (O.T.); (O.T.); (E.S.); (T.I.); (O.B.); (I.K.); (V.B.); (A.G.)
| | - Tatyana Ivashchenko
- D.O. Ott Research Institute for Obstetrics, Gynaecology and Reproductology, Mendeleevskaya Line 3, 199034 St. Petersburg, Russia; (P.K.); (E.V.); (O.T.); (O.T.); (E.S.); (T.I.); (O.B.); (I.K.); (V.B.); (A.G.)
| | - Aitalina Sukhomyasova
- Molecular Medicine and Human Genetics, Research Laboratory, Medical Institute, M.K. Ammosov North-Eastern Federal University, 677007 Yakutsk, Russia;
- Republican Hospital No. 1, National Medical Centre, Ministry of Public Health of the Sakha Republic, 677008 Yakutsk, Russia;
| | - Nadezhda Maksimova
- Republican Hospital No. 1, National Medical Centre, Ministry of Public Health of the Sakha Republic, 677008 Yakutsk, Russia;
| | - Olesya Bespalova
- D.O. Ott Research Institute for Obstetrics, Gynaecology and Reproductology, Mendeleevskaya Line 3, 199034 St. Petersburg, Russia; (P.K.); (E.V.); (O.T.); (O.T.); (E.S.); (T.I.); (O.B.); (I.K.); (V.B.); (A.G.)
| | - Igor Kogan
- D.O. Ott Research Institute for Obstetrics, Gynaecology and Reproductology, Mendeleevskaya Line 3, 199034 St. Petersburg, Russia; (P.K.); (E.V.); (O.T.); (O.T.); (E.S.); (T.I.); (O.B.); (I.K.); (V.B.); (A.G.)
| | - Vladislav Baranov
- D.O. Ott Research Institute for Obstetrics, Gynaecology and Reproductology, Mendeleevskaya Line 3, 199034 St. Petersburg, Russia; (P.K.); (E.V.); (O.T.); (O.T.); (E.S.); (T.I.); (O.B.); (I.K.); (V.B.); (A.G.)
| | - Andrey Glotov
- D.O. Ott Research Institute for Obstetrics, Gynaecology and Reproductology, Mendeleevskaya Line 3, 199034 St. Petersburg, Russia; (P.K.); (E.V.); (O.T.); (O.T.); (E.S.); (T.I.); (O.B.); (I.K.); (V.B.); (A.G.)
- Ltd NIPT, Bolshoi V.O. 90, Building 2 lit. 3, 199106 St. Petersburg, Russia; (N.D.); (A.C.)
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35
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Mitochondrial Transplantation as a Novel Therapeutic Strategy for Mitochondrial Diseases. Int J Mol Sci 2021; 22:ijms22094793. [PMID: 33946468 PMCID: PMC8124982 DOI: 10.3390/ijms22094793] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 04/26/2021] [Accepted: 04/27/2021] [Indexed: 02/06/2023] Open
Abstract
Mitochondria are the major source of intercellular bioenergy in the form of ATP. They are necessary for cell survival and play many essential roles such as maintaining calcium homeostasis, body temperature, regulation of metabolism and apoptosis. Mitochondrial dysfunction has been observed in variety of diseases such as cardiovascular disease, aging, type 2 diabetes, cancer and degenerative brain disease. In other words, the interpretation and regulation of mitochondrial signals has the potential to be applied as a treatment for various diseases caused by mitochondrial disorders. In recent years, mitochondrial transplantation has increasingly been a topic of interest as an innovative strategy for the treatment of mitochondrial diseases by augmentation and replacement of mitochondria. In this review, we focus on diseases that are associated with mitochondrial dysfunction and highlight studies related to the rescue of tissue-specific mitochondrial disorders. We firmly believe that mitochondrial transplantation is an optimistic therapeutic approach in finding a potentially valuable treatment for a variety of mitochondrial diseases.
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36
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Aliabadi F, Sohrabi B, Mostafavi E, Pazoki-Toroudi H, Webster TJ. Ubiquitin-proteasome system and the role of its inhibitors in cancer therapy. Open Biol 2021; 11:200390. [PMID: 33906413 PMCID: PMC8080017 DOI: 10.1098/rsob.200390] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Despite all the other cells that have the potential to prevent cancer development and metastasis through tumour suppressor proteins, cancer cells can upregulate the ubiquitin–proteasome system (UPS) by which they can degrade tumour suppressor proteins and avoid apoptosis. This system plays an extensive role in cell regulation organized in two steps. Each step has an important role in controlling cancer. This demonstrates the importance of understanding UPS inhibitors and improving these inhibitors to foster a new hope in cancer therapy. UPS inhibitors, as less invasive chemotherapy drugs, are increasingly used to alleviate symptoms of various cancers in malignant states. Despite their success in reducing the development of cancer with the lowest side effects, thus far, an appropriate inhibitor that can effectively inactivate this system with the least drug resistance has not yet been fully investigated. A fundamental understanding of the system is necessary to fully elucidate its role in causing/controlling cancer. In this review, we first comprehensively investigate this system, and then each step containing ubiquitination and protein degradation as well as their inhibitors are discussed. Ultimately, its advantages and disadvantages and some perspectives for improving the efficiency of these inhibitors are discussed.
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Affiliation(s)
- Fatemeh Aliabadi
- Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Beheshteh Sohrabi
- Department of Chemistry, Surface Chemistry Research Laboratory, Iran University of Science and Technology, PO Box 16846-13114, Tehran, Iran
| | - Ebrahim Mostafavi
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA.,Stanford Cardiovascular Institute, Stanford, CA, USA.,Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Hamidreza Pazoki-Toroudi
- Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Thomas J Webster
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA
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37
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Mitochondrial genome stability in human: understanding the role of DNA repair pathways. Biochem J 2021; 478:1179-1197. [DOI: 10.1042/bcj20200920] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 02/15/2021] [Accepted: 02/17/2021] [Indexed: 11/17/2022]
Abstract
Mitochondria are semiautonomous organelles in eukaryotic cells and possess their own genome that replicates independently. Mitochondria play a major role in oxidative phosphorylation due to which its genome is frequently exposed to oxidative stress. Factors including ionizing radiation, radiomimetic drugs and replication fork stalling can also result in different types of mutations in mitochondrial DNA (mtDNA) leading to genome fragility. Mitochondria from myopathies, dystonia, cancer patient samples show frequent mtDNA mutations such as point mutations, insertions and large-scale deletions that could account for mitochondria-associated disease pathogenesis. The mechanism by which such mutations arise following exposure to various DNA-damaging agents is not well understood. One of the well-studied repair pathways in mitochondria is base excision repair. Other repair pathways such as mismatch repair, homologous recombination and microhomology-mediated end joining have also been reported. Interestingly, nucleotide excision repair and classical nonhomologous DNA end joining are not detected in mitochondria. In this review, we summarize the potential causes of mitochondrial genome fragility, their implications as well as various DNA repair pathways that operate in mitochondria.
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38
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Skin Mirrors Brain: A Chance for Alzheimer’s Disease Research. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1339:371-380. [DOI: 10.1007/978-3-030-78787-5_45] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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39
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Bartho LA, Fisher JJ, Cuffe JSM, Perkins AV. Mitochondrial transformations in the aging human placenta. Am J Physiol Endocrinol Metab 2020; 319:E981-E994. [PMID: 32954826 DOI: 10.1152/ajpendo.00354.2020] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Mitochondria play a key role in homeostasis and are central to one of the leading hypotheses of aging, the free radical theory. Mitochondria function as a reticulated network, constantly adapting to the cellular environment through fusion (joining), biogenesis (formation of new mitochondria), and fission (separation). This adaptive response is particularly important in response to oxidative stress, cellular damage, and aging, when mitochondria are selectively removed through mitophagy, a mitochondrial equivalent of autophagy. During this complex process, mitochondria influence surrounding cell biology and organelles through the release of signaling molecules. Given that the human placenta is a unique organ having a transient and somewhat defined life span of ∼280 days, any adaption or dysfunction associated with mitochondrial physiology as a result of aging will have a dramatic impact on the health and function of both the placenta and the fetus. Additionally, a defective placenta during gestation, resulting in reduced fetal growth, has been shown to influence the development of chronic disease in later life. In this review we focus on the mitochondrial adaptions and transformations that accompany gestational length and share similarities with age-related diseases. In addition, we discuss the role of such changes in regulating placental function throughout gestation, the etiology of gestational complications, and the development of chronic diseases later in life.
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Affiliation(s)
- Lucy A Bartho
- School of Medical Science, Griffith University Gold Coast Campus, Southport, Queensland, Australia
| | - Joshua J Fisher
- Hunter Medical Research Institute and School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia
| | - James S M Cuffe
- School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia
| | - Anthony V Perkins
- School of Medical Science, Griffith University Gold Coast Campus, Southport, Queensland, Australia
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40
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Mitochondrial genomes of four American characins and phylogenetic relationships within the family Characidae (Teleostei: Characiformes). Gene 2020; 762:145041. [DOI: 10.1016/j.gene.2020.145041] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/11/2020] [Accepted: 08/04/2020] [Indexed: 01/08/2023]
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41
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Castora FJ, Conyers BL, Gershon BS, Kerns KA, Campbell R, Simsek-Duran F. The T9861C Mutation in the mtDNA-Encoded Cytochrome C Oxidase Subunit III Gene Occurs in High Frequency but with Unequal Distribution in the Alzheimer's Disease Brain. J Alzheimers Dis 2020; 72:257-269. [PMID: 31561357 DOI: 10.3233/jad-190176] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Mitochondrial dysfunction is recognized as a critical component in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Deficits in oxidative capacity and, specifically, cytochrome c oxidase (CO) activity have been reported in AD brains and platelets. We previously identified a point mutation at np 9861 in AD brain mitochondrial DNA (mtDNA) that alters amino acid 219 of subunit III of CO from phenylalanine to leucine. We rapidly screened and quantitated levels of T9861C in samples using mismatched PCR-RFLP and nucleotide extension assays. Six of 40 AD brains possessed the T9861C mutation (designated AD+) compared to zero of 40 age-matched control brains. The 15% frequency of T9861C in AD brain is 115-fold higher than the frequency (0.13%) reported in 9,986 human mtDNA samples queried in world-wide databases. T9861C is heteroplasmic, with mutant load varying from 11% to >95%. Detected initially in parietal cortex, T9861C is not localized to that region but is also found in temporal cortex and caudate but not in hippocampus. The mutant load is unequally distributed throughout these brain regions with the highest load occurring in the parietal or temporal cortex. CO activity normalized to citrate synthase (CS) is reduced an average of 48.5% in AD+ brains. CO/CS ratios amongst controls and the two AD populations (AD and AD+) were significantly different (p = 0.001). Post hoc differences were also significant between controls and AD+ (p = 0.001) and controls and AD (p = 0.019). There was no significant difference between AD and AD+ (p = 0.317).
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Affiliation(s)
- Frank J Castora
- Department of Physiological Sciences, Division of Biochemistry, Eastern Virginia Medical School, Norfolk, VA, USA.,Department of Neurology, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Barbara L Conyers
- Department of Physiological Sciences, Division of Biochemistry, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Blake S Gershon
- Department of Physiological Sciences, Division of Biochemistry, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Kimberly A Kerns
- Department of Physiological Sciences, Division of Biochemistry, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Robert Campbell
- School of Health Professions, MPH Program, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Fatma Simsek-Duran
- Department of Physiological Sciences, Division of Biochemistry, Eastern Virginia Medical School, Norfolk, VA, USA
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Lujan SA, Longley MJ, Humble MH, Lavender CA, Burkholder A, Blakely EL, Alston CL, Gorman GS, Turnbull DM, McFarland R, Taylor RW, Kunkel TA, Copeland WC. Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging. Genome Biol 2020; 21:248. [PMID: 32943091 PMCID: PMC7500033 DOI: 10.1186/s13059-020-02138-5] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 08/07/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Acquired human mitochondrial genome (mtDNA) deletions are symptoms and drivers of focal mitochondrial respiratory deficiency, a pathological hallmark of aging and late-onset mitochondrial disease. RESULTS To decipher connections between these processes, we create LostArc, an ultrasensitive method for quantifying deletions in circular mtDNA molecules. LostArc reveals 35 million deletions (~ 470,000 unique spans) in skeletal muscle from 22 individuals with and 19 individuals without pathogenic variants in POLG. This nuclear gene encodes the catalytic subunit of replicative mitochondrial DNA polymerase γ. Ablation, the deleted mtDNA fraction, suffices to explain skeletal muscle phenotypes of aging and POLG-derived disease. Unsupervised bioinformatic analyses reveal distinct age- and disease-correlated deletion patterns. CONCLUSIONS These patterns implicate replication by DNA polymerase γ as the deletion driver and suggest little purifying selection against mtDNA deletions by mitophagy in postmitotic muscle fibers. Observed deletion patterns are best modeled as mtDNA deletions initiated by replication fork stalling during strand displacement mtDNA synthesis.
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Affiliation(s)
- Scott A Lujan
- Genome Integrity and Structural Biology Laboratory, DNA Replication Fidelity Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA
| | - Matthew J Longley
- Genome Integrity and Structural Biology Laboratory, Mitochondrial DNA Replication Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA
| | - Margaret H Humble
- Genome Integrity and Structural Biology Laboratory, Mitochondrial DNA Replication Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA
| | - Christopher A Lavender
- Integrative Bioinformatics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA
| | - Adam Burkholder
- Integrative Bioinformatics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA
| | - Emma L Blakely
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
- NHS Highly Specialised Mitochondrial Diagnostic Laboratory, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK
| | - Charlotte L Alston
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
- NHS Highly Specialised Mitochondrial Diagnostic Laboratory, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK
| | - Grainne S Gorman
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Doug M Turnbull
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Robert McFarland
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Robert W Taylor
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
- NHS Highly Specialised Mitochondrial Diagnostic Laboratory, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK
| | - Thomas A Kunkel
- Genome Integrity and Structural Biology Laboratory, DNA Replication Fidelity Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA
| | - William C Copeland
- Genome Integrity and Structural Biology Laboratory, Mitochondrial DNA Replication Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.
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Ziada AS, Smith MSR, Côté HCF. Updating the Free Radical Theory of Aging. Front Cell Dev Biol 2020; 8:575645. [PMID: 33043009 PMCID: PMC7525146 DOI: 10.3389/fcell.2020.575645] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 08/18/2020] [Indexed: 11/13/2022] Open
Affiliation(s)
- Adam S Ziada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
| | - Marie-Soleil R Smith
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
| | - Hélène C F Côté
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.,Women's Health Research Institute, Vancouver, BC, Canada
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44
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Asally R, Markham R, Manconi F. Mitochondrial DNA haplogroup H association with endometriosis and possible role in inflammation and pain. JOURNAL OF ENDOMETRIOSIS AND PELVIC PAIN DISORDERS 2020. [DOI: 10.1177/2284026520940518] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Introduction: Endometriosis is an inflammatory disease characterised by the presence of endometrial-like tissue outside the uterus and affects approximately 10%–15% of women in their reproductive years. Pain is one of the predominant symptoms of the disease. Oxidative stress is involved in the pathophysiology of endometriosis and develops when there is an imbalance between the reactive oxygen species and reactive nitrogen species production, and the elimination capacity of antioxidants in the reproductive tract. High levels of reactive oxygen species can induce pain indirectly through oxidative stress-associated inflammation or directly through sensitising the nociceptive neurons that transmit the signals to the cerebral sensory cortex which are perceived as a feeling of pain. Mitochondria are the main source of reactive oxygen species, which generate through oxidative phosphorylation. Given that the mitochondria are involved in reactive oxygen species formation and energy production, which are required for the activation and proliferation of peripheral lymphocytes, it has been suggested that mitochondrial DNA variants are involved in the pathogenesis of endometriosis. This study has provided a better understanding of maternally inherited risk factors which contribute to the pain mechanisms associated with endometriosis. Results: Mitochondrial DNA haplogroup H was found to be significantly higher in women with endometriosis. This study was the first to report the association between the European mitochondrial haplogroup H and the risk of pain associated with endometriosis. Discussion: The results suggest that there are maternally inherited risk factors in women with endometriosis causing high reactive oxygen species production and oxidative stress, which facilitate pain generation in women with endometriosis.
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Affiliation(s)
- Razan Asally
- Discipline of Obstetrics, Gynaecology and Neonatology, The University of Sydney, Camperdown, NSW, Australia
- Saudi Arabian Ministry of Higher Education, Riyadh, Saudi Arabia
| | - Robert Markham
- Discipline of Obstetrics, Gynaecology and Neonatology, The University of Sydney, Camperdown, NSW, Australia
| | - Frank Manconi
- Discipline of Obstetrics, Gynaecology and Neonatology, The University of Sydney, Camperdown, NSW, Australia
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Age-Related Deterioration of Mitochondrial Function in the Intestine. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:4898217. [PMID: 32922652 PMCID: PMC7453234 DOI: 10.1155/2020/4898217] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 07/22/2020] [Indexed: 12/29/2022]
Abstract
Aging is an important and inevitable biological process in human life, associated with the onset of chronic disease and death. The mechanisms behind aging remain unclear. However, changes in mitochondrial function and structure, including reduced activity of the mitochondrial respiratory chain and increased production of reactive oxygen species—thus oxidative damage—are believed to play a major role. Mitochondria are the main source of cellular energy, producing adenosine triphosphate (ATP) via oxidative phosphorylation. Accumulation of damaged cellular components reduces a body's capacity to preserve tissue homeostasis and affects biological aging and all age-related chronic conditions. This includes the onset and progression of classic degenerative diseases such as cardiovascular disease, kidney failure, neurodegenerative diseases, and cancer. Clinical manifestations of intestinal disorders, such as mucosal barrier dysfunction, intestinal dysmotility, and chronic obstipation, are highly prevalent in the elderly population and have been shown to be associated with an age-dependent decline of mitochondrial function. This review summarizes our current understanding of the role of mitochondrial dysfunction in intestinal aging.
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46
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Balcázar M, Cañizares S, Borja T, Pontón P, Bisiou S, Carabasse E, Bacilieri A, Canavese C, Diaz RF, Cabrera F, Caicedo A. Bases for Treating Skin Aging With Artificial Mitochondrial Transfer/Transplant (AMT/T). Front Bioeng Biotechnol 2020; 8:919. [PMID: 32903493 PMCID: PMC7438394 DOI: 10.3389/fbioe.2020.00919] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 07/16/2020] [Indexed: 12/13/2022] Open
Abstract
The perception of mitochondria as only the powerhouse of the cell has dramatically changed in the last decade. It is now accepted that in addition to being essential intracellularly, mitochondria can promote cellular repair when transferred from healthy to damaged cells. The artificial mitochondria transfer/transplant (AMT/T) group of techniques emulate this naturally occurring process and have been used to develop therapies to treat a range of diseases including cardiac and neurodegenerative. Mitochondria accumulate damage with time, resulting in cellular senescence. Skin cells and its mitochondria are profoundly affected by ultraviolet radiation and other factors that induce premature and accelerated aging. In this article, we propose the basis to use AMT/T to treat skin aging by transferring healthy mitochondria to senescent cells, possibly revitalizing them. We provide insightful information about how skin structure, components, and cells could age rapidly depending on the amount of damage received. Arguments are shown in favor of the use of AMT/T to treat aging skin and its cells, among them the possibility to stop free radical production, add new genetic material, and provide an energetic boost to help cells prolong their viability over time. This article intends to present one of the many aspects in which mitochondria could be used as a universal treatment for cell and tissue damage and aging.
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Affiliation(s)
- Micaela Balcázar
- Escuela de Medicina, Colegio de Ciencias de la Salud COCSA, Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | - Stalin Cañizares
- Escuela de Medicina, Colegio de Ciencias de la Salud COCSA, Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | - Tatiana Borja
- Servicio de Patología, Hospital Voz Andes, Quito, Ecuador.,CEDIA-USFQ Research Initiative, Corporación Ecuatoriana para el Desarrollo de la Investigación y Académica CEDIA and Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | - Patricia Pontón
- Servicio de Patología, Hospital Voz Andes, Quito, Ecuador.,CEDIA-USFQ Research Initiative, Corporación Ecuatoriana para el Desarrollo de la Investigación y Académica CEDIA and Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | - Sirivanh Bisiou
- Université de Montpellier, Faculté de Medicine, Montpellier, France
| | - Eva Carabasse
- Université de Montpellier, Faculté de Medicine, Montpellier, France
| | - Angela Bacilieri
- Université de Montpellier, Faculté de Medicine, Montpellier, France
| | - Celia Canavese
- Université de Montpellier, Faculté de Medicine, Montpellier, France
| | - Ramiro F Diaz
- Escuela de Medicina Veterinaria, Colegio de Ciencias de la Salud COCSA, Universidad San Francisco de Quito USFQ, Quito, Ecuador.,Instituto de Investigaciones en Biomedicina, Universidad San Francisco de Quito USFQ, Quito, Ecuador.,Mito-Act Research Consortium, Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | - Francisco Cabrera
- Escuela de Medicina Veterinaria, Colegio de Ciencias de la Salud COCSA, Universidad San Francisco de Quito USFQ, Quito, Ecuador.,Instituto de Investigaciones en Biomedicina, Universidad San Francisco de Quito USFQ, Quito, Ecuador.,Mito-Act Research Consortium, Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | - Andrés Caicedo
- Escuela de Medicina, Colegio de Ciencias de la Salud COCSA, Universidad San Francisco de Quito USFQ, Quito, Ecuador.,CEDIA-USFQ Research Initiative, Corporación Ecuatoriana para el Desarrollo de la Investigación y Académica CEDIA and Universidad San Francisco de Quito USFQ, Quito, Ecuador.,Instituto de Investigaciones en Biomedicina, Universidad San Francisco de Quito USFQ, Quito, Ecuador.,Mito-Act Research Consortium, Universidad San Francisco de Quito USFQ, Quito, Ecuador.,Sistemas Médicos SIME, Universidad San Francisco de Quito USFQ, Quito, Ecuador
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47
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Mitochondria, spermatogenesis, and male infertility - An update. Mitochondrion 2020; 54:26-40. [PMID: 32534048 DOI: 10.1016/j.mito.2020.06.003] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 06/02/2020] [Accepted: 06/08/2020] [Indexed: 12/14/2022]
Abstract
The incorporation of mitochondria in the eukaryotic cell is one of the most enigmatic events in the course of evolution. This important organelle was thought to be only the powerhouse of the cell, but was later learnt to perform many other indispensable functions in the cell. Two major contributions of mitochondria in spermatogenesis concern energy production and apoptosis. Apart from this, mitochondria also participate in a number of other processes affecting spermatogenesis and fertility. Mitochondria in sperm are arranged in the periphery of the tail microtubules to serve to energy demand for motility. Apart from this, the role of mitochondria in germ cell proliferation, mitotic regulation, and the elimination of germ cells by apoptosis are now well recognized. Eventually, mutations in the mitochondrial genome have been reported in male infertility, particularly in sluggish sperm (asthenozoospermia); however, heteroplasmy in the mtDNA and a complex interplay between the nucleus and mitochondria affect their penetrance. In this article, we have provided an update on the role of mitochondria in various events of spermatogenesis and male fertility and on the correlation of mitochondrial DNA mutations with male infertility.
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48
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Bueno M, Calyeca J, Rojas M, Mora AL. Mitochondria dysfunction and metabolic reprogramming as drivers of idiopathic pulmonary fibrosis. Redox Biol 2020; 33:101509. [PMID: 32234292 PMCID: PMC7251240 DOI: 10.1016/j.redox.2020.101509] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 03/13/2020] [Accepted: 03/16/2020] [Indexed: 02/07/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. It is characterized by deposition of extracellular matrix proteins, like collagen and fibronectin in the lung interstitium leading to respiratory failure. Our understanding of the pathobiology underlying IPF is still incomplete; however, it is accepted that aging is a major risk factor in the disease while growing evidence suggests that the mitochondria plays an important role in the initiation and progression of pulmonary fibrosis. Mitochondria dysfunction and metabolic reprogramming had been identified in different IPF lung cells (alveolar epithelial cells, fibroblasts, and macrophages) promoting low resilience and increasing susceptibility to activation of profibrotic responses. Here we summarize changes in mitochondrial numbers, biogenesis, turnover and associated metabolic adaptations that promote disrepair and fibrosis in the lung. Finally, we highlight new possible therapeutic approaches focused on ameliorate mitochondrial dysfunction.
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Affiliation(s)
- Marta Bueno
- Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jazmin Calyeca
- Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mauricio Rojas
- Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Dorothy and Richard Simmons Center for Interstitial Lung Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ana L Mora
- Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
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49
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Cappa R, de Campos C, Maxwell AP, McKnight AJ. "Mitochondrial Toolbox" - A Review of Online Resources to Explore Mitochondrial Genomics. Front Genet 2020; 11:439. [PMID: 32457801 PMCID: PMC7225359 DOI: 10.3389/fgene.2020.00439] [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: 10/24/2019] [Accepted: 04/09/2020] [Indexed: 12/30/2022] Open
Abstract
Mitochondria play a significant role in many biological systems. There is emerging evidence that differences in the mitochondrial genome may contribute to multiple common diseases, leading to an increasing number of studies exploring mitochondrial genomics. There is often a large amount of complex data generated (for example via next generation sequencing), which requires optimised bioinformatics tools to efficiently and effectively generate robust outcomes from these large datasets. Twenty-four online resources dedicated to mitochondrial genomics were reviewed. This 'mitochondrial toolbox' summary resource will enable researchers to rapidly identify the resource(s) most suitable for their needs. These resources fulfil a variety of functions, with some being highly specialised. No single tool will provide all users with the resources they require; therefore, the most suitable tool will vary between users depending on the nature of the work they aim to carry out. Genetics resources are well established for phylogeny and DNA sequence changes, but further epigenetic and gene expression resources need to be developed for mitochondrial genomics.
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Affiliation(s)
- Ruaidhri Cappa
- Centre for Public Health, Institute of Clinical Sciences B, Queen's University Belfast, Royal Victoria Hospital, Belfast, United Kingdom
| | - Cassio de Campos
- School of Electronics, Electrical Engineering and Computer Science, Queen's University Belfast, Belfast, United Kingdom
| | - Alexander P Maxwell
- Centre for Public Health, Institute of Clinical Sciences B, Queen's University Belfast, Royal Victoria Hospital, Belfast, United Kingdom
| | - Amy J McKnight
- Centre for Public Health, Institute of Clinical Sciences B, Queen's University Belfast, Royal Victoria Hospital, Belfast, United Kingdom
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50
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Ding X, Liu X, Wang F, Wang F, Geng X. Role of Senescence and Neuroprotective Effects of Telomerase in Neurodegenerative Diseases. Rejuvenation Res 2020; 23:150-158. [DOI: 10.1089/rej.2018.2115] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Xuelu Ding
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China
| | - Xuewen Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China
| | - Feng Wang
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Fei Wang
- Department of Neurology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Xin Geng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China
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