Abstract
Point mutations and deletions of mitochondrial DNA (mtDNA) accumulate in a variety of tissues during ageing in humans1, monkeys2 and rodents3. These mutations are unevenly distributed and can accumulate clonally in certain cells, causing a mosaic pattern of respiratory chain deficiency in tissues such as heart4, skeletal muscle5 and brain6. In terms of the ageing process, their possible causative effects have been intensely debated because of their low abundance and purely correlative connection with ageing7,8. We have now addressed this question experimentally by creating homozygous knock-in mice that express a proof-reading-deficient version of PolgA, the nucleus-encoded catalytic subunit of mtDNA polymerase. Here we show that the knock-in mice develop an mtDNA mutator phenotype with a threefold to fivefold increase in the levels of point mutations, as well as increased amounts of deleted mtDNA. This increase in somatic mtDNA mutations is associated with reduced lifespan and premature onset of ageing-related phenotypes such as weight loss, reduced subcutaneous fat, alopecia (hair loss), kyphosis (curvature of the spine), osteoporosis, anaemia, reduced fertility and heart enlargement. Our results thus provide a causative link between mtDNA mutations and ageing phenotypes in mammals.
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Acknowledgements
H.T.J, N.G.L and J.T are supported by the European Union MitAGE project. N.G.L is supported by the Swedish Research Council, the Göran Gustafsson Foundation for Research in Natural Sciences and Medicine, the Torsten and Ragnar Söderbergs Foundation, the Swedish Heart and Lung Foundation, the Swedish Foundation for Strategic Research (Functional Genomics and INGVAR) and Funds of Karolinska Institutet. J.N.S and H.T.J are supported by the Academy of Finland and Tampere University Hospital Medical Research Fund. R.W is supported by Funds of Karolinska Institutet and FreeMason's In Stockholm Foundation for Children's Wellfare. A.O is supported by the Swedish Research Council. We thank B. Rozell for mouse pathology evaluation, S. Horttanainen, Z. Cansu, V. Edrisi and M. Åkerberg for technical assistance, and the Karolinska Center for Transgene Technologies for technical assistance.
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We have filed a patent application covering potential commercial uses of the mtDNA mutator mice.
Supplementary information
Supplementary Figure 1
Characterization of mtDNA deletions (PDF 1919 kb)
Supplementary Figure 2
Biochemical measurement of respiratory chain function (PDF 123 kb)
Supplementary Table 1
Haematology (DOC 20 kb)
Supplementary Table 2
Absolute organ weights (DOC 21 kb)
Supplementary Table 3
Organ weights in relation to body weight (DOC 22 kb)
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Trifunovic, A., Wredenberg, A., Falkenberg, M. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004). https://doi.org/10.1038/nature02517
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DOI: https://doi.org/10.1038/nature02517
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