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Mitochondrial point mutations do not limit the natural lifespan of mice

Nature Genetics volume 39, pages 540543 (2007) | Download Citation

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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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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

Affiliations

  1. Department of Pathology, University of Washington, Seattle, Washington 91895, USA.

    • Marc Vermulst
    • , Jason H Bielas
    • , Peter S Rabinovitch
    •  & Lawrence A Loeb
  2. Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, Wisconsin 53706, USA.

    • Gregory C Kujoth
    •  & Tomas A Prolla
  3. Department of Comparative Medicine, University of Washington, Seattle, Washington 98195, USA.

    • Warren C Ladiges

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Lawrence A Loeb.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    RMC protocol.

  2. 2.

    Supplementary Fig. 2

    PCR artificially raises the mutation frequency.

  3. 3.

    Supplementary Fig. 3

    Treatment of mtDNA with hydrogen peroxide does not affect the performance of the RMC assay.

  4. 4.

    Supplementary Fig. 4

    Decreased mutation frequency in hearts of mCAT animals

  5. 5.

    Supplementary Fig. 5

    Mutation spectra of wild-type, exonuclease-deficient and mCAT animals.

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    Supplementary Fig. 6

    Mutation frequencies at three additional loci in Polg+/mut mice.

  7. 7.

    Supplementary Table 1

    Control and TaqI flanking primers.

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DOI

https://doi.org/10.1038/ng1988

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