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Cited by 555Mitochondrial Function and PathologyGenetics, Aging, and Longevity in Model OrganismsTelomeres, Telomerase, and Senescence

Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production

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Trifunovic, Aleksandra, Hansson, Anna, Wredenberg, Anna, Rovio, Anja T., Dufour, Eric, Khvorostov, Ivan, Spelbrink, Johannes N., Wibom, Rolf +2 more·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0508886102PMC PMC1312403
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Abstract

The mitochondrial theory of aging proposes that reactive oxygen species (ROS) generated inside the cell will lead, with time, to increasing amounts of oxidative damage to various cell components. The main site for ROS production is the respiratory chain inside the mitochondria and accumulation of mtDNA mutations, and impaired respiratory chain function have been associated with degenerative diseases and aging. The theory predicts that impaired respiratory chain function will augment ROS production and thereby increase the rate of mtDNA mutation accumulation, which, in turn, will further compromise respiratory chain function. Previously, we reported that mice expressing an error-prone version of the catalytic subunit of mtDNA polymerase accumulate a substantial burden of somatic mtDNA mutations, associated with premature aging phenotypes and reduced lifespan. Here we show that these mtDNA mutator mice accumulate mtDNA mutations in an approximately linear manner. The amount of ROS produced was normal, and no increased sensitivity to oxidative stress-induced cell death was observed in mouse embryonic fibroblasts from mtDNA mutator mice, despite the presence of a severe respiratory chain dysfunction. Expression levels of antioxidant defense enzymes, protein carbonylation levels, and aconitase enzyme activity measurements indicated no or only minor oxidative stress in tissues from mtDNA mutator mice. The premature aging phenotypes in mtDNA mutator mice are thus not generated by a vicious cycle of massively increased oxidative stress accompanied by exponential accumulation of mtDNA mutations. We propose instead that respiratory chain dysfunction per se is the primary inducer of premature aging in mtDNA mutator mice.

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  • There are no changes in the levels of antioxidants, protein carbonyls or aconitase enzyme activity in tissues of mtDNA mutator mice.

    “There are also no changes in the levels of antioxidants, protein carbonyls or aconitase enzyme activity in their tissues.”

    From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Trifunovic et al., 2005

  • Mouse embryonic fibroblasts from mtDNA mutator mice produce normal amounts of ROS and demonstrate no increased sensitivity to oxidative stress.

    “In a follow-up study to experimentally address the “vicious” cycle aspect of the MFRTA, mouse embryonic fibroblasts from mtDNA mutator mice are shown to produce normal amounts of ROS and demonstrate no increased sensitivity to oxidative stress (Trifunovic et al., 2005).”

    From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Trifunovic et al., 2005

  • The progeroid phenotype and accumulated mutations of mtDNA mutator mice are not due to increased ROS production and oxidative stress.

    “The progeroid phenotype and accumulated mutations of mtDNA mutator mice are not due to increased ROS production and oxidative stress (Trifunovic et al., 2005).”

    From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Trifunovic et al., 2005

  • Normal levels of ROS were measured in POLG1 mutator mice, which eventually accumulate sufficient mtDNA mutations to cause severe OXPHOS deficiency.

    “Conversely, normal levels of ROS were measured in the POLG1 mutator mice, which eventually accumulate sufficient mtDNA mutations to cause severe OXPHOS deficiency [189].”

    From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [189]

  • Mouse models with decreased mtDNA expression have increased cell death with little or no increase of oxidative stress.

    “We have studied a variety of mouse models with decreased mtDNA expression (10, 12–18) and such mice have increased cell death with little or no increase of oxidative stress (18, 30).”

    From Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons (2007) · cites this paper as [30]

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Authors
Trifunovic, A., Hansson, A., Wredenberg, A., Rovio, A. T., Dufour, E., Khvorostov, I., Spelbrink, J. N., Wibom, R., Jacobs, H. T., & Larsson, N.-G.
Affiliations
  • Department of Laboratory Medicine, Karolinska Institute, S-141 86 Stockholm, Sweden; and Institute of Medical Technology and Tampere University Hospital, FI-33014 University of Tampere, Finland
  • Karolinska Institutet (SE)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-12-06
Volume
102
Issue
50
Pages
17993-17998
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0508886102
PMC
PMC1312403
OpenAlex
W2118939556
Cited by
555
References
49
Citations by year
2026: 5 · 2025: 14 · 2024: 18 · 2023: 8 · 2022: 13 · 2021: 23 · 2020: 24 · 2019: 15 · 2018: 26 · 2017: 17 · 2016: 28 · 2015: 35 · 2014: 36 · 2013: 36 · 2012: 30
FWCI
14.43
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
somatic mtDNA mutations, premature aging, mitochondrial theory of aging, reactive oxygen species, respiratory chain deficiency, oxidative stress, antioxidant enzymes, protein carbonylation, aconitase activity, lifespan, mouse embryonic fibroblasts
MeSH terms
Aging, Analysis of Variance, Animals, Cells, Cultured, DNA Mutational Analysis, DNA, Mitochondrial, Fibroblasts, Mice, Mutant Strains, Mutation, Oxygen Consumption, Blotting, Northern, Blotting, Western, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Mitochondrial Diseases, Protein Carbonylation, Mice

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