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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 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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Figure 1: Frequency of mitochondrial mutations as a function of age.
Figure 2: Mitochondrial mutation spectrum in wild-type animals.
Figure 3: Kaplan-Meier survival curves.
Figure 4: Mutation burden in wild-type and Polg exonuclease–deficient mice.

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Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Contributions

M.V. carried out all the experiments described and wrote the paper. M.V., J.H.B. and L.A.L. conceived the project. G.C.K. and T.A.P. provided Kaplan-Meier curves and statistical analysis of mouse cohorts. J.H.B., W.C.L., G.C.K., T.A.P. and P.S.R. provided technical assistance, animal care and tissues. L.A.L. supervised the experimental work and interpretation of data. All authors commented on and discussed the paper.

Corresponding author

Correspondence to Lawrence A Loeb.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

RMC protocol. (PDF 182 kb)

Supplementary Fig. 2

PCR artificially raises the mutation frequency. (PDF 93 kb)

Supplementary Fig. 3

Treatment of mtDNA with hydrogen peroxide does not affect the performance of the RMC assay. (PDF 78 kb)

Supplementary Fig. 4

Decreased mutation frequency in hearts of mCAT animals (PDF 50 kb)

Supplementary Fig. 5

Mutation spectra of wild-type, exonuclease-deficient and mCAT animals. (PDF 85 kb)

Supplementary Fig. 6

Mutation frequencies at three additional loci in Polg+/mut mice. (PDF 99 kb)

Supplementary Table 1

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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  • DOI: https://doi.org/10.1038/ng1988

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