Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function
Abstract
Although mitochondrial DNA deletions have been shown to accumulate in cytochrome c oxidase deficient muscle fibres of ageing muscle, this has not been demonstrated for point mutations. In this study, we investigated the occurrence of mitochondrial DNA alterations (point mutations and deletions) in cytochrome c oxidase deficient muscle fibres from 14 individuals, without muscle disease, aged 69-82 years. Immunohistochemical investigation showed that the majority of the cytochrome c oxidase deficient muscle fibres expressed reduced levels of subunit II of cytochrome c oxidase, which is encoded by mitochondrial DNA, whereas there was normal or increased expression of subunit IV of cytochrome c oxidase, which is encoded by nuclear DNA. This pattern is typical for mitochondrial DNA mutations causing impaired mitochondrial translation. Single muscle fibres (109 cytochrome c oxidase deficient and 109 normal fibres) were dissected and their DNA extracted. Mitochondrial DNA point mutations were searched for in five tRNA genes by denaturing gradient gel electrophoresis while deletions were looked for by polymerase chain reaction amplification. High levels of clonally expanded point mutations were identified in eight cytochrome c oxidase deficient fibres but in none of the normal ones. They included the previously described pathogenic tRNALeu(UUR)A3243G and tRNALysA8344G mutations and three original mutations: tRNAMetT4460C, tRNAMetG4421A, and a 3-bp deletion in the tRNALeu(UUR) gene. Four different large-scale mitochondrial DNA deletions were identified in seven cytochrome c oxidase deficient fibres and in one of the normal ones. There was no evidence of depletion of mitochondrial DNA by in situ hybridisation experiments. Our data show that mitochondrial DNA point mutations, as well as large-scale deletions, are associated with cytochrome c oxidase deficient muscle fibre segments in ageing. Their focal accumulation causes significant impairment of mitochondrial function in individual cells in spite of low overall levels of mitochondrial DNA mutations in muscle.
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Accumulations of mtDNA damage in the form of point mutations, deletions and depletions are correlated with aging and age-related diseases as observed in human skeletal muscle, liver, brain, heart, skin fibroblasts and colonic crypt stem cells.
“Accumulations of mtDNA damage in the form of point mutations, deletions and depletions are correlated with aging and age-related diseases as observed in human skeletal muscle (Bua et al., 2006; Fayet et al., 2002), liver (Yen et al., 1991), brain (Corral-Debrinski et al., 1992a; Corral-Debrinski et al., 1994; Lin et al., 2002), heart (Corral-Debrinski et al., 1992b; Cortopassi and Arnheim, 1990),”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Fayet et al., 2002
Clonal expansion of mtDNA mutations has been described in numerous tissues from aged individuals, including skeletal muscle, substantia nigra neurons, heart and colonic crypts.
“Clonal expansion of mtDNA mutations has been described in numerous tissues from aged individuals, such as skeletal muscle (Fayet et al., 2002; Muller-Hocker et al., 1993), substantia nigra neurons (Cottrell et al., 2001; Kraytsberg et al., 2006), heart (Muller-Hocker, 1989) and colonic crypts (Taylor et al., 2003).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Fayet et al., 2002
Cites
Goto, Y.-I., Nonaka, I., & Horai, S. (1990) · Nature · doi:10.1038/348651a0 · Cited by 2,070 · see citing works
Shoffner, J. M., Lott, M. T., Lezza, A. M. S., Seibel, P., Ballinger, S. W., & Wallace, D. C. (1990) · Cell · doi:10.1016/0092-8674(90)90059-n · Cited by 1,468 · see citing works
Mitochondrial Genetics: A Paradigm for Aging and Degenerative Diseases?
Wallace, D. C. (1992) · Science · doi:10.1126/science.1533953 · Cited by 1,256 · see citing works
MITOCHONDRIAL DNA MUTATIONS AS AN IMPORTANT CONTRIBUTOR TO AGEING AND DEGENERATIVE DISEASES
Linnane, A. W., Ozawa, T., Marzuki, S., & Tanaka, M. (1989) · The Lancet · doi:10.1016/s0140-6736(89)92145-4 · Cited by 1,192 · see citing works
Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease
Mecocci, P., MacGarvey, U., & Beal, M. F. (1994) · Annals of Neurology · doi:10.1002/ana.410360510 · Cited by 1,037 · see citing works
Detection of a specific mitochondrial DNA deletion in tissues of older humans
Cortopassi, G. A., & Arnheim, N. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.23.6927 · Cited by 785 · see citing works
Michikawa, Y., Mazzucchelli, F., Bresolin, N., Scarlato, G., & Attardi, G. M. (1999) · Science · doi:10.1126/science.286.5440.774 · Cited by 725 · see citing works
A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues.
Cortopassi, G. A., Shibata, D. K., Soong, N.-W., & Arnheim, N. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.16.7370 · Cited by 639 · see citing works
Mitochondrial DNA Variants Observed in Alzheimer Disease and Parkinson Disease Patients
Shoffner, J. M., Brown, M. D., Torroni, A., Lott, M. T., Cabell, M. F., Mirra, S. S., Beal, M. F., Yang, C.-C., Gearing, M., Salvo, R., et al. (1993) · Genomics · doi:10.1006/geno.1993.1299 · Cited by 450 · see citing works
Majamaa, K., Moilanen, J. S., Uimonen, S., Remes, A. M., Salmela, P. I., Kärppä, M., Majamaa‐Voltti, K., Rusanen, H., Sorri, M., PEUHKURINEN, K. J., et al. (1998) · The American Journal of Human Genetics · doi:10.1086/301959 · Cited by 385 · see citing works
Mitochondrial oxidative phosphorylation defects in parkinson's disease
Shoffner, J. M., Watts, R. L., Juncos, J. L., Torroni, A., & Wallace, D. C. (1991) · Annals of Neurology · doi:10.1002/ana.410300304 · Cited by 333 · see citing works
Progressive Increase of the Mutated Mitochondrial DNA Fraction in Kearns-Sayre Syndrome
Larsson, N.-G., Holme, E., Kristiansson, B., Oldfors, A., & Tulinius, M. (1990) · Pediatric Research · doi:10.1203/00006450-199008000-00011 · Cited by 324 · see citing works
Self-citationMitochondrial DNA transmission of the mitochondrial defect in Parkinson's disease
Gu, M., Cooper, J. A. D., Taanman, J., & Schapira, A. H. V. (1998) · Annals of Neurology · doi:10.1002/ana.410440207 · Cited by 313 · see citing works
Sciacco, M., Bonilla, E., Schon, E. A., DiMauro, S., & Moraes, C. T. (1994) · Human Molecular Genetics · doi:10.1093/hmg/3.1.13 · Cited by 305 · see citing works
Müller‐Höcker, J. (1990) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(90)90006-9 · Cited by 284 · see citing works
Brierley, E. J., Johnson, M. A., Lightowlers, R. N., James, O., & Turnbull, D. M. (1998) · Annals of Neurology · doi:10.1002/ana.410430212 · Cited by 282 · see citing works
Wang, Y., Michikawa, Y., Mallidis, C., Bai, Y., Woodhouse, L. J., Yarasheski, K. E., Miller, C. A., Askanas, V., Engel, W. K., Bhasin, S., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.061013598 · Cited by 272 · see citing works
Melov, S., Shoffner, J. M., Kaufman, A. E., & Wallace, D. C. (1995) · Nucleic Acids Research · doi:10.1093/nar/23.20.4122 · Cited by 271 · see citing works
Hattori, K., Tanaka, M., Sugiyama, S., Obayashi, T., Ito, T., Satake, T., Hanaki, Y., Asai, J., Nagano, M., & Ozawa, T. (1991) · American Heart Journal · doi:10.1016/0002-8703(91)90020-i · Cited by 264 · see citing works
Multiple mitochondrial DNA deletions in an elderly human individual
Zhang, C., Baumer, A., Maxwell, R. J., Linnane, A. W., & Nagley, P. (1992) · FEBS Letters · doi:10.1016/0014-5793(92)80321-7 · Cited by 214 · see citing works
Mita, S., Schmidt, B., Schon, E. A., DiMauro, S., & Bonilla, E. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.23.9509 · Cited by 211 · see citing works
Relaxed Replication of mtDNA: A Model with Implications for the Expression of Disease
Chinnery, P. F., & Samuels, D. C. (1999) · The American Journal of Human Genetics · doi:10.1086/302311 · Cited by 200 · see citing works
Liu, V. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.5.1268 · Cited by 168 · see citing works
Mitochondrial gene mutation: the ageing process and degenerative diseases.
Linnane, A. W., Baumer, A., Maxwell, R. J., Preston, H. S., Zhang, C. F., & Marzuki, S. (1990) · PubMed · Cited by 165 · see citing works
Mitochondria in neuromuscular disorders
DiMauro, S., Bonilla, E., Davidson, M. M., Hirano, M., & Schon, E. A. (1998) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(98)00113-3 · Cited by 157 · see citing works
Münscher, C., Rieger, T., Müller‐Höcker, J., & Kadenbach, B. (1993) · FEBS Letters · doi:10.1016/0014-5793(93)81484-h · Cited by 143 · see citing works
Zhang, C., Linnane, A. W., & Nagley, P. (1993) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1993.2158 · Cited by 134 · see citing works
Cytochrome c oxidase deficient cells accumulate in the hippocampus and choroid plexus with age
Cottrell, D. A., Blakely, E. L., Johnson, M. A., Ince, P. G., Borthwick, G. M., & Turnbull, D. M. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00234-7 · Cited by 132 · see citing works
Petruzzella, V., Moraes, C. T., Sano, M. C., Bonilla, S., DiMauro, S., & Schon, E. A. (1994) · Human Molecular Genetics · doi:10.1093/hmg/3.3.449 · Cited by 118 · see citing works
Mitochondrial DNA Deletions in Muscle Fibers in Inclusion Body Myositis
Oldfors, A., Moslemi, A., Fyhr, I., Holme, E., Larsson, N., & Lindberg, C. (1995) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199507000-00012 · Cited by 115 · see citing works
Self-citationMurdock, D. G. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.21.4350 · Cited by 110 · see citing works
Pallotti, F., Chen, X., Bonilla, E., & Schon, E. A. (1996) · PubMed Central · Cited by 93 · see citing works
Moslemi, A., Oldfors, A., Melberg, A., & Holme, E. (1996) · Annals of Neurology · doi:10.1002/ana.410400506 · Cited by 91 · see citing works
Self-citationCarrozzo, R., Hirano, M., Fromenty, B., Casali, C., Santorelli, F. M., Bonilla, E., DiMauro, S., Schon, E. A., & Miranda, A. F. (1998) · Neurology · doi:10.1212/wnl.50.1.99 · Cited by 79 · see citing works
Baumer, A., Zhang, C., Linnane, A. W., & Nagley, P. (1994) · PubMed Central · Cited by 78 · see citing works
Revolution in mitochondrial medicine
Larsson, N., & Luft, R. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00854-6 · Cited by 76 · see citing works
Sternberg, D., Danan, C., Lombès, A., et al. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.1.33 · Cited by 75 · see citing works
Self-citationBiochemical and molecular analysis of cytochrome c oxidase deficiency in Leigh's syndrome
Lombès, A., Nakase, H., Tritschler, H.-J., et al. (1991) · Neurology · doi:10.1212/wnl.41.4.491 · Cited by 71 · see citing works
Self-citationMitochondrial DNA deletions and cytochrome c oxidase deficiency in muscle fibres
Oldfors, A., Larsson, N., Holme, E., Tulinius, M., Kadenbach, B., & Droste, M. (1992) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(92)90025-g · Cited by 61 · see citing works
Self-citationBodyak, N. D. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.1.17 · Cited by 55 · see citing works
Replication-Competent Human Mitochondrial DNA Lacking the Heavy-Strand Promoter Region
Moraes, C. T., Andreetta, F., Bonilla, E., Shanske, S., DiMauro, S., & Schon, E. A. (1991) · Molecular and Cellular Biology · doi:10.1128/mcb.11.3.1631 · Cited by 48 · see citing works
Threshold expression of the tRNALys A8344G mutation in single muscle fibres
Moslemi, A., Tulinius, M., Holme, E., & Oldfors, A. (1998) · Neuromuscular Disorders · doi:10.1016/s0960-8966(98)00029-7 · Cited by 47 · see citing works
Self-citationImmunohistochemical analysis of muscle cytochromec oxidase deficiency in children
Possekel, S., Lombès, A., de Baulny, H. O., et al. (1995) · Histochemistry and Cell Biology · doi:10.1007/bf01464476 · Cited by 26 · see citing works
Self-citation
Flagged first, then by citations
Cited by
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Premature ageing in mice expressing defective mitochondrial DNA polymerase
Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly-Y, M., Gidlöf, S., Oldfors, A., Wibom, R., et al. (2004) · Nature · doi:10.1038/nature02517 · Cited by 2,734 · see citing works
Self-citationThe role of mitochondria in aging
Bratic, A., & Larsson, N.-G. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64125 · Cited by 1,087 · see citing works
A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease
Swerdlow, R. H., & Khan, S. M. (2004) · Medical Hypotheses · doi:10.1016/j.mehy.2003.12.045 · Cited by 758 · see citing works
Mammalian Mitochondria and Aging: An Update
Kauppila, T. E. S., Kauppila, J. H. K., & Larsson, N.-G. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.017 · Cited by 578 · see citing works
Bua, E., Johnson, J., Herbst, A., Delong, B., McKenzie, D., Salamat, S., & Aiken, J. M. (2006) · The American Journal of Human Genetics · doi:10.1086/507132 · Cited by 442 · see citing works
Mitophagy: An Emerging Role in Aging and Age-Associated Diseases
Chen, G., Kroemer, G., & Kepp, O. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00200 · Cited by 359 · see citing works
Mitophagy in neurodegeneration and aging
Fivenson, E. M., Lautrup, S., Sun, N., Scheibye-Knudsen, M., Stevnsner, T., Nilsen, H., Bohr, V. A., & Fang, E. F. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.02.007 · Cited by 364 · see citing works
Mitochondrial dysfunction in aging: Much progress but many unresolved questions
Payne, B. A. I., & Chinnery, P. F. (2015) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.05.022 · Cited by 335 · see citing works
HIONA, A. (2008) · Experimental Gerontology · doi:10.1016/j.exger.2007.10.001 · Cited by 247 · see citing works
Parkinson’s disease as a result of aging
Rodriguez, M., Rodriguez‐Sabate, C., Morales, I., Sanchez, A., & Sabate, M. (2015) · Aging Cell · doi:10.1111/acel.12312 · Cited by 214 · see citing works
DeBalsi, K. L., Hoff, K. E., & Copeland, W. C. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.04.006 · Cited by 180 · see citing works
Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis
Biniecka, M., Fox, E., Gao, W., Ng, C. T., Veale, D. J., Fearon, U., & O'Sullivan, J. (2011) · Arthritis & Rheumatism · doi:10.1002/art.30395 · Cited by 109 · see citing works
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Lauri, A., Pompilio, G., & Capogrossi, M. C. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.07.001 · Cited by 80 · see citing works
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Desler, C., Marcker, M. L., Singh, K. K., & Rasmussen, L. J. (2011) · Journal of Aging Research · doi:10.4061/2011/407536 · Cited by 49 · see citing works
Sevini, F., Giuliani, C., Vianello, D., Giampieri, E., Santoro, A., Biondi, F., Garagnani, P., Passarino, G., Luiselli, D., Capri, M., et al. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.03.022 · Cited by 46 · see citing works
Plataki, M., Cho, S. J., Harris, R. M., Huang, H.-R., Yun, H. S., Schiffer, K. T., & Stout-Delgado, H. W. (2019) · Scientific Reports · doi:10.1038/s41598-018-37438-1 · Cited by 42 · see citing works
- Authors
- Fayet, G., Jansson, M., Sternberg, D., Moslemi, A.-R., Blondy, P., Lombès, A., Fardeau, M., & Oldfors, A.
- Affiliations
- Inserm (FR)
- Sahlgrenska University Hospital (SE)
- Laboratoire de Biochimie (FR)
- Venue
- Neuromuscular Disorders
- Publisher
- Elsevier BV
- Published
- 2002-06
- Volume
- 12
- Issue
- 5
- Pages
- 484-493
- ISSN
- 0960-8966 (ISSN-L)
- OpenAlex
- W2036988144
- Cited by
- 206
- References
- 43
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 8 · 2023: 5 · 2022: 11 · 2021: 7 · 2020: 12 · 2019: 4 · 2018: 14 · 2017: 4 · 2016: 7 · 2015: 8 · 2014: 11 · 2013: 10 · 2012: 9
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuromuscular Disorders (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fondation pour la Recherche Médicale
- Reumatikerförbundet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Keywords
- mitochondrial DNA mutations, mitochondrial DNA deletions, cytochrome c oxidase deficiency, clonal expansion, cytochrome c oxidase subunit II, mitochondrial function, skeletal muscle fibers
- MeSH terms
- Aged, Aged, 80 and over, Aging, Base Sequence, Electron Transport Complex IV, DNA, Mitochondrial, Female, Humans, Isoenzymes, Male, Mitochondria, Muscle, Gene Deletion, Point Mutation, Muscle, Skeletal, Muscle Fibers, Skeletal, Mitochondrial Diseases, Cytochrome-c Oxidase Deficiency
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