Ageing is due to an accumulation of various types of damage1,2, and mitochondrial dysfunction has long been considered to be important in this process3,4,5,6,7,8. There is substantial sequence variation in mammalian mitochondrial DNA (mtDNA)9, and the high mutation rate is counteracted by different mechanisms that decrease maternal transmission of mutated mtDNA10,11,12,13. Despite these protective mechanisms14, it is becoming increasingly clear that low-level mtDNA heteroplasmy is quite common and often inherited in humans15,16. We designed a series of mouse mutants to investigate the extent to which inherited mtDNA mutations can contribute to ageing. Here we report that maternally transmitted mtDNA mutations can induce mild ageing phenotypes in mice with a wild-type nuclear genome. Furthermore, maternally transmitted mtDNA mutations lead to anticipation of reduced fertility in mice that are heterozygous for the mtDNA mutator allele (PolgAwt/mut) and aggravate premature ageing phenotypes in mtDNA mutator mice (PolgAmut/mut). Unexpectedly, a combination of maternally transmitted and somatic mtDNA mutations also leads to stochastic brain malformations. Our findings show that a pre-existing mutation load will not only allow somatic mutagenesis to create a critically high total mtDNA mutation load sooner but will also increase clonal expansion of mtDNA mutations17 to enhance the normally occurring mosaic respiratory chain deficiency in ageing tissues18,19. Our findings suggest that maternally transmitted mtDNA mutations may have a similar role in aggravating aspects of normal human ageing.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Szilard, L. On the nature of the aging process. Proc. Natl Acad. Sci. USA 45, 30–45 (1959)
Kirkwood, T. B. L. Understanding the odd science of aging. Cell 120, 437–447 (2005)
Ernster, L., Löw, H., Nordenbrand, K. & Ernster, B. A component promoting oxidative phosphorylation, released from mitochondria during aging. Exp. Cell Res. 9, 348–349 (1955)
Miquel, J., Economos, A. C., Fleming, J. & Johnson, J. E. Mitochondrial role in cell aging. Exp. Gerontol. 15, 575–591 (1980)
Pikó, L., Hougham, A. J. & Bulpitt, K. J. Studies of sequence heterogeneity of mitochondrial DNA from rat and mouse tissues: evidence for an increased frequency of deletions/additions with aging. Mech. Ageing Dev. 43, 279–293 (1988)
Müller-Höcker, J. Cytochrome-c-oxidase deficient cardiomyocytes in the human heart — an age-related phenomenon. Am. J. Pathol. 134, 1167–1173 (1989)
Cortopassi, G. A. & Arnheim, N. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res. 18, 6927–6933 (1990)
Corral-Debrinski, M. et al. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nature Genet. 2, 324–329 (1992)
Pakendorf, B. & Stoneking, M. Mitochondrial DNA and human evolution. Annu. Rev. Genomics Hum. Genet. 6, 165–183 (2005)
Krakauer, D. C. & Mira, A. Mitochondria and germ-cell death. Nature 400, 125–126 (1999)
Stewart, J. B. et al. Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol. 6, e10 (2008)
Fan, W. et al. A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319, 958–962 (2008)
Freyer, C. et al. Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission. Nature Genet. 44, 1282–1285 (2012)
Stewart, J. B., Freyer, C., Elson, J. L. & Larsson, N.-G. Purifying selection of mtDNA and its implications for understanding evolution and mitochondrial disease. Nature Rev. Genet. 9, 657–662 (2008)
Li, M. et al. Detecting heteroplasmy from high-throughput sequencing of complete human mitochondrial DNA genomes. Am. J. Hum. Genet. 87, 237–249 (2010)
Payne, B. A. I. et al. Universal heteroplasmy of human mitochondrial DNA. Hum. Mol. Genet. 22, 384–390 (2013)
Payne, B. A. I. et al. Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nature Genet. 43, 806–810 (2011)
Greaves, L. C. & Turnbull, D. M. Mitochondrial DNA mutations and ageing. Biochim. Biophys. Acta 1790, 1015–1020 (2009)
Larsson, N. G. Somatic mitochondrial DNA mutations in mammalian aging. Annu. Rev. Biochem. 79, 683–706 (2010)
Ameur, A. et al. Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins. PLoS Genet. 7, e1002028 (2011)
Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004)
Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005)
Hance, N., Ekstrand, M. I. & Trifunovic, A. Mitochondrial DNA polymerase gamma is essential for mammalian embryogenesis. Hum. Mol. Genet. 14, 1775–1783 (2005)
Kraytsberg, Y. & Khrapko, K. Single-molecule PCR: an artifact-free PCR approach for the analysis of somatic mutations. Expert Rev. Mol. Diagn. 5, 809–815 (2005)
Greaves, L. C. et al. Quantification of mitochondrial DNA mutation load. Aging Cell 8, 566–572 (2009)
Greaves, L. C., Elson, J. L., Nooteboom, M. & Grady, J. P. Comparison of mitochondrial mutation spectra in ageing human colonic epithelium and disease: absence of evidence for purifying selection in somatic mitochondrial DNA point mutations. PLoS Genet. 8, e1003082 (2012)
Taylor, R. W. et al. Mitochondrial DNA mutations in human colonic crypt stem cells. J. Clin. Invest. 112, 1351–1360 (2003)
Ahlqvist, K. J. et al. Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. Cell Metab. 15, 100–109 (2012)
Norddahl, G. L. et al. Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. Stem Cells 8, 499–510 (2011)
Chen, M. L. et al. Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction. Blood 114, 4045–4053 (2009)
Hancock, D. K., Tully, L. A. & Levin, B. C. A Standard Reference Material to determine the sensitivity of techniques for detecting low-frequency mutations, SNPs, and heteroplasmies in mitochondrial DNA. Genomics 86, 446–461 (2005)
Wanrooij, S. et al. In vivo mutagenesis reveals that OriL is essential for mitochondrial DNA replication. EMBO Rep. 13, 1130–1137 (2012)
Ross, J. M. et al. High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio. Proc. Natl Acad. Sci. USA 107, 20087–20092 (2010)
The study was supported by ERC Advanced Investigator grants (268897 to N.-G.L. and 322744 to L.O.), the Swedish Research Council (K2011-62X-21870-01-6 to N.-G.L. and K2012-62X-03185-42-4 to L.O.), the Swedish Brain Foundation (N.-G.L. and J.M.R.), Swedish Brain Power (L.O. and J.M.R.), the Swedish Parkinson Foundation (N.-G.L.), the Karolinska Distinguished Professor Award (L.O.), the Swedish Alzheimer Foundation (L.O.) the National Institutes of Health (AG04418 to L.O. and NS070825 to B.J.H.), the National Institute on Drug Abuse (J.M.R.), the National Institutes of Health/Karolinska Institutet Graduate Partnerships Program (J.M.R.) and the Swedish Society for Medical Research (G.C.). J.B.S. acknowledges support from the United Mitochondrial Disease Foundation.
The authors declare no competing financial interests.
About this article
Cite this article
Ross, J., Stewart, J., Hagström, E. et al. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501, 412–415 (2013). https://doi.org/10.1038/nature12474
Smart treatment strategies for alleviating tauopathy and neuroinflammation to improve clinical outcome in Alzheimer's disease
Drug Discovery Today (2020)
Environmental Science & Technology Letters (2020)
Age‐induced mitochondrial DNA point mutations are inadequate to alter metabolic homeostasis in response to nutrient challenge
Aging Cell (2020)
Ageing Research Reviews (2020)
Ageing Research Reviews (2020)