Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Germline mitochondrial DNA mutations aggravate ageing and can impair brain development



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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

Figure 1: Breeding to generate mice with different combinations of maternally inherited and somatic mtDNA mutations.
Figure 2: Anticipation of reduced fecundity obtained by intercrossing of heterozygous mtDNA mutator mice.
Figure 3: Premature ageing phenotypes in mice with a wild-type nuclear genome and in mtDNA mutator mice.
Figure 4: Focal and symmetric brain malformations in mtDNA mutator mice.


  1. Szilard, L. On the nature of the aging process. Proc. Natl Acad. Sci. USA 45, 30–45 (1959)

    Article  ADS  CAS  Google Scholar 

  2. Kirkwood, T. B. L. Understanding the odd science of aging. Cell 120, 437–447 (2005)

    Article  CAS  Google Scholar 

  3. 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)

    Article  CAS  Google Scholar 

  4. Miquel, J., Economos, A. C., Fleming, J. & Johnson, J. E. Mitochondrial role in cell aging. Exp. Gerontol. 15, 575–591 (1980)

    Article  CAS  Google Scholar 

  5. 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)

    Article  Google Scholar 

  6. Müller-Höcker, J. Cytochrome-c-oxidase deficient cardiomyocytes in the human heart — an age-related phenomenon. Am. J. Pathol. 134, 1167–1173 (1989)

    PubMed  PubMed Central  Google Scholar 

  7. Cortopassi, G. A. & Arnheim, N. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res. 18, 6927–6933 (1990)

    Article  CAS  Google Scholar 

  8. Corral-Debrinski, M. et al. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nature Genet. 2, 324–329 (1992)

    Article  CAS  Google Scholar 

  9. Pakendorf, B. & Stoneking, M. Mitochondrial DNA and human evolution. Annu. Rev. Genomics Hum. Genet. 6, 165–183 (2005)

    Article  CAS  Google Scholar 

  10. Krakauer, D. C. & Mira, A. Mitochondria and germ-cell death. Nature 400, 125–126 (1999)

    Article  ADS  CAS  Google Scholar 

  11. Stewart, J. B. et al. Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol. 6, e10 (2008)

    Article  Google Scholar 

  12. Fan, W. et al. A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319, 958–962 (2008)

    Article  ADS  CAS  Google Scholar 

  13. Freyer, C. et al. Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission. Nature Genet. 44, 1282–1285 (2012)

    Article  CAS  Google Scholar 

  14. 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)

    Article  CAS  Google Scholar 

  15. Li, M. et al. Detecting heteroplasmy from high-throughput sequencing of complete human mitochondrial DNA genomes. Am. J. Hum. Genet. 87, 237–249 (2010)

    Article  CAS  Google Scholar 

  16. Payne, B. A. I. et al. Universal heteroplasmy of human mitochondrial DNA. Hum. Mol. Genet. 22, 384–390 (2013)

    Article  CAS  Google Scholar 

  17. 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)

    Article  CAS  Google Scholar 

  18. Greaves, L. C. & Turnbull, D. M. Mitochondrial DNA mutations and ageing. Biochim. Biophys. Acta 1790, 1015–1020 (2009)

    Article  CAS  Google Scholar 

  19. Larsson, N. G. Somatic mitochondrial DNA mutations in mammalian aging. Annu. Rev. Biochem. 79, 683–706 (2010)

    Article  CAS  Google Scholar 

  20. Ameur, A. et al. Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins. PLoS Genet. 7, e1002028 (2011)

    Article  CAS  Google Scholar 

  21. Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004)

    Article  ADS  CAS  Google Scholar 

  22. Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005)

    Article  ADS  CAS  Google Scholar 

  23. Hance, N., Ekstrand, M. I. & Trifunovic, A. Mitochondrial DNA polymerase gamma is essential for mammalian embryogenesis. Hum. Mol. Genet. 14, 1775–1783 (2005)

    Article  CAS  Google Scholar 

  24. 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)

    Article  CAS  Google Scholar 

  25. Greaves, L. C. et al. Quantification of mitochondrial DNA mutation load. Aging Cell 8, 566–572 (2009)

    Article  CAS  Google Scholar 

  26. 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)

    Article  CAS  Google Scholar 

  27. Taylor, R. W. et al. Mitochondrial DNA mutations in human colonic crypt stem cells. J. Clin. Invest. 112, 1351–1360 (2003)

    Article  CAS  Google Scholar 

  28. 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)

    Article  CAS  Google Scholar 

  29. 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)

    CAS  Google Scholar 

  30. Chen, M. L. et al. Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction. Blood 114, 4045–4053 (2009)

    Article  CAS  Google Scholar 

  31. 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)

    Article  CAS  Google Scholar 

  32. Wanrooij, S. et al. In vivo mutagenesis reveals that OriL is essential for mitochondrial DNA replication. EMBO Rep. 13, 1130–1137 (2012)

    Article  CAS  Google Scholar 

  33. 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)

    Article  ADS  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



J.M.R., J.B.S. and G.C. performed breeding and phenotypic analyses of mice. J.B.S., E.H. and C.F. performed mtDNA sequence analysis. J.M.R., J.B.S. and S.B. performed histology and MRI analyses. A.M. and M.L. performed molecular analyses and measurement of respiratory chain function. J.M.R., J.B.S., B.J.H., L.O. and N.-G.L. conceived the ideas, designed the experiments and wrote the paper.

Corresponding authors

Correspondence to Lars Olson or Nils-Göran Larsson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-4 and Supplementary Tables 1-3. (PDF 942 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing