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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Corral-Debrinski, M. et al. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nature Genet. 2, 324–329 (1992)
Schwarze, S. R. et al. High levels of mitochondrial DNA deletions in skeletal muscle of old rhesus monkeys. Mech. Ageing Dev. 83, 91–101 (1995)
Khaidakov, M., Heflich, R. H., Manjanatha, M. G., Myers, M. B. & Aidoo, A. Accumulation of point mutations in mitochondrial DNA of aging mice. Mutat. Res. 526, 1–7 (2003)
Mueller-Hocker, J. Cytochrome-c-oxidase deficient cardiomyocytes in the human heart—An age-related phenomenon. Am. J. Pathol. 134, 1167–1173 (1989)
Fayet, G. et al. Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function. Neuromuscul. Disord. 12, 484–493 (2002)
Cottrell, D. A. et al. Cytochrome c oxidase deficient cells accumulate in the hippocampus and choroid plexus with age. Neurobiol. Aging 22, 265–272 (2001)
Cottrell, D. A. & Turnbull, D. M. Mitochondria and ageing. Curr. Opin. Clin. Nutr. Metab. Care 3, 473–478 (2000)
Wallace, D. C. A mitochondrial paradigm for degenerative diseases and ageing. Novartis Found. Symp. 235, 247–263 (2001)
Carrodeguas, J. A., Kobayashi, R., Lim, S. E., Copeland, W. C. & Bogenhagen, D. F. The accessory subunit of Xenopus laevis mitochondrial DNA polymerase γ increases processivity of the catalytic subunit of human DNA polymerase γ and is related to class II aminoacyl-tRNA synthetases. Mol. Cell. Biol. 19, 4039–4046 (1999)
Foury, F. & Vanderstraeten, S. Yeast mitochondrial DNA mutators with deficient proofreading exonucleolytic activity. EMBO J. 11, 2717–2726 (1992)
Vanderstraeten, S., Van den Brule, S., Hu, J. & Foury, F. The role of 3′-5′ exonucleolytic proofreading and mismatch repair in yeast mitochondrial DNA error avoidance. J. Biol. Chem. 273, 23690–23697 (1998)
Rodriguez, C. I. et al. High-efficiency deleter mice show that FLPe is an alternative to Cre– loxP. Nature Genet. 25, 139–140 (2000)
Meyers, E. N., Lewandoski, M. & Martin, G. R. An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination. Nature Genet. 18, 136–141 (1998)
Kalu, D. N. Handbook of Physiology section 11 Aging (Oxford Univ. Press, New York, 1995)
Arking, R. Biology of Aging (Sinauer, Sunderland, Massachusetts, 1998)
Haines, D. C., Chattopadhyay, S. & Ward, J. M. Pathology of aging B6;129 mice. Toxicol. Pathol. 29, 653–661 (2001)
Weiss, A., Arbell, I., Steinhagen-Thiessen, E. & Silbermann, M. Structural changes in aging bone: osteopenia in the proximal femurs of female mice. Bone 12, 165–172 (1991)
Balducci, L. Epidemiology of anemia in the elderly: information on diagnostic evaluation. J. Am. Geriatr. Soc. 51, S2–S9 (2003)
Braunwald, E. (ed.) Heart Disease. A Textbook of Cardiovascular Medicine (W.B. Saunders Co., Philadelphia, 1997)
Pal, L. & Santoro, N. Age-related decline in fertility. Endocrinol. Metab. Clin. North Am. 32, 669–688 (2003)
Tanemura, K., Kurohmaru, M., Kuramoto, K. & Hayashi, Y. Age-related morphological changes in the testis of the BDF1 mouse. J. Vet. Med. Sci. 55, 703–710 (1993)
Larsson, N. G. et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nature Genet. 18, 231–236 (1998)
Silva, J. P. et al. Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial diabetes. Nature Genet. 26, 336–340 (2000)
Sorensen, L. et al. Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice. J. Neurosci. 21, 8082–8090 (2001)
Hansson, A. et al. A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts. Proc. Natl Acad. Sci. USA 101, 3136–3141 (2004)
Wredenberg, A. et al. Increased mitochondrial mass in mitochondrial myopathy mice. Proc. Natl Acad. Sci. USA 99, 15066–15071 (2002)
Wang, J., Silva, J., Gustafsson, C. M., Rustin, P. & Larsson, N. G. Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression. Proc. Natl Acad. Sci. USA 98, 4038–4043 (2001)
Spelbrink, J. N. et al. In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells. J. Biol. Chem. 275, 24818–24828 (2000)
Bibb, M. J., VanEtten, R. A., Wright, C. T., Walberg, M. W. & Clayton, D. A. Sequence and organization of mouse mitochondrial DNA. Cell 26, 167–180 (1981)
Wibom, R., Hagenfeldt, L. & von Dobeln, U. Measurement of ATP production and respiratory chain enzyme activities in mitochondria isolated from small muscle biopsy samples. Anal. Biochem. 311, 139–151 (2002)
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.
We have filed a patent application covering potential commercial uses of the mtDNA mutator mice.
Characterization of mtDNA deletions (PDF 1919 kb)
Biochemical measurement of respiratory chain function (PDF 123 kb)
Haematology (DOC 20 kb)
Absolute organ weights (DOC 21 kb)
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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