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DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice

Nature Genetics volume 40, pages 392–394 (2008)Cite this article

Abstract

Mitochondrial DNA (mtDNA) mutations are thought to have a causal role in many age-related pathologies. Here we identify mtDNA deletions as a driving force behind the premature aging phenotype of mitochondrial mutator mice, and provide evidence for a homology-directed DNA repair mechanism in mitochondria that is directly linked to the formation of mtDNA deletions. In addition, our results demonstrate that the rate at which mtDNA mutations reach phenotypic expression differs markedly among tissues, which may be an important factor in determining the tolerance of a tissue to random mitochondrial mutagenesis.

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Figure 1: Mitochondrial deletion load and spectrum in WT, Polga+/mut and Polgamut/mut mice.
Figure 2: Tissue distribution of COX-negative cells.

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Acknowledgements

This work was supported by grants AG01751 (L.A.L. and P.S.R.), CA102029 and ES11045 (L.A.L.) and AG021905 (T.A.P. and G.C.K.) from the US National Institutes of Health. J.H.B. is a Research Fellow of the Terry Fox Foundation through an award from the National Cancer Institute of Canada. J.W. was supported by the Brookdale Leadership Aging Fellowship. The authors thank R.S. Mangalindan, C. Masuda and N. Ericson for technical assistance.

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Authors and Affiliations

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

    Marc Vermulst, Jason H Bielas, Peter S Rabinovitch & Lawrence A Loeb

  2. Department of Gerontology and Geriatric Medicine, University of Washington, Seattle, 91895, Washington, USA

    Jonathan Wanagat

  3. Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, 53706, Wisconsin, USA

    Gregory C Kujoth & Tomas A Prolla

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  1. Marc Vermulst
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  2. Jonathan Wanagat
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  3. Gregory C Kujoth
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  4. Jason H Bielas
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  7. Lawrence A Loeb
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Contributions

M.V. carried out the experiments described in Figures 1a and b, Supplementary Figures 1,2,3,4,5 and Supplementary Tables 1 and 2. M.V. adapted the RMC-assay and wrote the paper. J.W. and M.V. generated Figure 2 and Supplementary Figures 6 and 7. M.V., J.H.B. and L.A.L. conceived the project. J.H.B. performed cell culture and provided technical expertise. G.C.K., T.A.P. and P.S.R. provided animal care, tissues and technical assistance. L.A.L. supervised the experimental work and interpretation of the data. All authors commented on and discussed the paper.

Note: Supplementary information is available on the Nature Genetics website.

Corresponding author

Correspondence to Lawrence A Loeb.

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Supplementary Methods, Supplementary Figures 1–7, Supplementary Tables 1 and 2 (PDF 908 kb)

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Vermulst, M., Wanagat, J., Kujoth, G. et al. DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice. Nat Genet 40, 392–394 (2008). https://doi.org/10.1038/ng.95

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