Whether mitochondrial mutations cause mammalian aging, or are merely correlated with it, is an area of intense debate1. Here, we use a new, highly sensitive assay2 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 mouse3 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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This work was supported by US National Institutes of Health grants AG001751 (L.A.L., P.S.R.), CA102029 (L.A.L.), ES11045 (L.A.L., W.C.L.) and AG021905 (T.A.P., G.C.K.). J.H.B. was supported by a research fellowship from the Canadian Institutes of Health. The authors thank G.M. Martin, R.S. Mangalindan, R.N. Venkatesan and C.-Y. Chen for editing this manuscript, technical assistance and discussions.
The authors declare no competing financial interests.
RMC protocol. (PDF 182 kb)
PCR artificially raises the mutation frequency. (PDF 93 kb)
Treatment of mtDNA with hydrogen peroxide does not affect the performance of the RMC assay. (PDF 78 kb)
Decreased mutation frequency in hearts of mCAT animals (PDF 50 kb)
Mutation spectra of wild-type, exonuclease-deficient and mCAT animals. (PDF 85 kb)
Mutation frequencies at three additional loci in Polg+/mut mice. (PDF 99 kb)
Control and TaqI flanking primers. (PDF 39 kb)
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Vermulst, M., Bielas, J., Kujoth, G. et al. Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet 39, 540–543 (2007). https://doi.org/10.1038/ng1988
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