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Germline mitochondrial DNA mutations aggravate ageing and can impair brain development

Nature volume 501, pages 412–415 (2013)Cite this article

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Abstract

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.

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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.

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Acknowledgements

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.

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Author notes

  1. Jaime M. Ross and James B. Stewart: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden,

    Jaime M. Ross, Giuseppe Coppotelli & Lars Olson

  2. Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany,

    James B. Stewart, Arnaud Mourier, Christoph Freyer, Marie Lagouge & Nils-Göran Larsson

  3. Department of Laboratory Medicine, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden,

    Erik Hagström, Christoph Freyer & Nils-Göran Larsson

  4. Department of Neurobiology, Care Sciences, and Society, KERIC, Karolinska Institutet, 171 76 Stockholm, Sweden,

    Stefan Brené

  5. Department of Neurosurgery, University Hospitals, Case Western Reserve Medical Center, 11100 Eucid Avenue, Cleveland, Ohio 44106, USA,

    Barry J. Hoffer

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  1. Jaime M. Ross
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Contributions

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.

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The authors declare no competing financial interests.

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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

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