Mitochondrial point mutations do not limit the natural lifespan of mice
Abstract
Whether mitochondrial mutations cause mammalian aging, or are merely correlated with it, is an area of intense debate. Here, we use a new, highly sensitive assay to redefine the relationship between mitochondrial mutations and age. We measured the in vivo rate of change of the mitochondrial genome at a single-base pair level in mice, and we demonstrate that the mutation frequency in mouse mitochondria is more than ten times lower than previously reported. Although we observed an 11-fold increase in mitochondrial point mutations with age, we report that a mitochondrial mutator mouse was able to sustain a 500-fold higher mutation burden than normal mice, without any obvious features of rapidly accelerated aging. Thus, our results strongly indicate that mitochondrial mutations do not limit the lifespan of wild-type mice.
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Correlative evidence between increased levels of 8-oxo-dG and age-related deletions in mtDNA from humans, mice, rats and houseflies has been reported.
“Correlative evidence between increased levels of 8-oxo-dG and age-related deletions in mtDNA from humans (Capel et al., 2005; Hayakawa et al., 1992; Hayakawa et al., 1991), mice (Vermulst et al., 2007), rats (Sawada and Carlson, 1987) and houseflies (Sohal and Sohal, 1991) has been reported.”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Vermulst et al., 2007
Using the random capture method, heterozygous Pol γ mutant mice are found to have a 500-fold higher mutational burden than age-matched wild-type controls and a 30-fold increase over the oldest wild-type animals.
“However, using an adaptation of the more sensitive “random capture method,” which relies on PCR amplification of single molecules for mutation detection but is not limited by polymerase fidelity, the heterozygous mice are found to have a 500-fold higher mutational burden than age-matched wild-type controls and a 30-fold increase over the oldest wild-type animals (Vermulst et al., 2007).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Vermulst et al., 2007
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References 30 · Cited by 404
- Authors
- Vermulst, M., Bielas, J. H., Kujoth, G. C., Ladiges, W. C., Rabinovitch, P. S., Prolla, T. A., & Loeb, L. A.
- Affiliations
- University of Washington (US)
- University of Wisconsin–Madison (US)
- Corresponding author
- Loeb, Lawrence A
- Venue
- Nature Genetics
- Published
- 2007-03-04
- Volume
- 39
- Issue
- 4
- Pages
- 540-543
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2000730064
- Cited by
- 404
- References
- 30
- Citations by year
- 2026: 8 · 2025: 23 · 2024: 13 · 2023: 16 · 2022: 11 · 2021: 17 · 2020: 15 · 2019: 19 · 2018: 22 · 2017: 21 · 2016: 11 · 2015: 25 · 2014: 23 · 2013: 15 · 2012: 18
- FWCI
- 10.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG021905, AG001751, P01AG001751, AG021905)
- National Cancer Institute (CA-102029, R01CA102029)
- National Institute of Environmental Health Sciences (U01ES011045, ES11045)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- mitochondrial genome, aging, lifespan, mutation rate
- MeSH terms
- DNA Polymerase gamma, Aging, Animals, Cells, Cultured, DNA-Directed DNA Polymerase, Longevity, Mice, Transgenic, Mitochondria, Point Mutation, Mice
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