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Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice

Abstract

Several lines of evidence indicate an association between mitochondrial DNA (mtDNA) and the functioning of the nervous system. As neuronal development1,2 and structure3,4,5 as well as axonal and synaptic activity6,7 involve mitochondrial genes, it is not surprising that most mtDNA diseases are associated with brain disorders8,9. Only one study has suggested an association between mtDNA and cognition10, however. Here we provide direct evidence of mtDNA involvement in cognitive functioning. Total substitution of mtDNA was achieved by 20 repeated backcrosses in NZB/BlNJ (N) and CBA/H (H) mice with different mtDNA origins. All 13 mitochondrial genes were expressed in the brains of the congenic quartet. In interaction with nuclear DNA (nDNA), mtDNA modified learning, exploration, sensory development and the anatomy of the brain. The effects of mtDNA substitution persisted with age, increasing in magnitude as the mice got older. We observed different effects with input of mtDNA from N versus H mice, varying according to the phenotypes. Exchanges of mtDNA may produce phenotypes outside the range of scores observed in the original mitochondrial and nuclear combinations. These findings show that mitochondrial polymorphisms are not as neutral as was previously believed.

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Figure 1: Learning performance in the radial maze, the Krushinsky task and the Morris water maze (mean ± s.e.m.) in H (red), HmtDNA N (blue), N (green) and NmtDNA H (yellow) strains.
Figure 2: Exploratory activity in three tasks (mean ± s.e.m.) in H (red), HmtDNA N (blue), N (green) and NmtDNA H (yellow) mice at 3, 6 and 12 months of age.
Figure 3: Brain morphometry at 5–6 months of age (n = 15–19 mice per group; mean ± s.e.m.) in H (red), HmtDNA N (blue), N (green) and NmtDNA H (yellow) mice.
Figure 4: Expression of the 13 mitochondrial genes encoding polypeptides in the brain of in the four strains.

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References

  1. Zini, R. et al. Resveratrol-induced limitation of dysfunction of mitochondrial isolated from rat brain in an anoxia-reoxygenation model. Life Sci. 71, 3091–3108 (2002).

    Article  CAS  Google Scholar 

  2. Atamna, H., Killilea, D.W., Killilea, A.N. & Ames, B.N. Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging. Proc. Natl. Acad. Sci. USA 99, 14807–14812 (2002).

    Article  CAS  Google Scholar 

  3. Johnson, B.D. & Bierly, L. A cytoskeletal mechanism for Ca2+ channels metabolic dependence and inactivation by intracellular Ca2+. Neuron 10, 797–804 (1993).

    Article  CAS  Google Scholar 

  4. Liu, J. et al. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-α-lipoic acid. Proc. Natl. Acad. Sci. USA 99, 2356–2361 (2002).

    Article  CAS  Google Scholar 

  5. Bristow, E.A., Griffiths, P.G., Andrews, R.M., Johnson, M.A. & Turnbull, D.M. The distribution of mitochondrial activity in relation to optic nerve structure. Arch. Ophtalmol. 120, 791–796 (2002)

    Article  Google Scholar 

  6. Zenisek, D. & Matthews, G. The role of mitochondria in presynaptic calcium handling at a ribbon synapse. Neuron 25, 229–237 (2000).

    Article  CAS  Google Scholar 

  7. Freeman, F.M. & Young, I.G. The mitochondrial benzodiazepine receptor and avoidance learning in the day-old chick. Pharmacol. Biochem. Behav. 67, 355–362 (2000).

    Article  CAS  Google Scholar 

  8. Wallace, D.C. Mitochondrial diseases in man and mouse. Science 283, 1482–1488 (1999).

    Article  CAS  Google Scholar 

  9. Schon, E.A. Mitochondrial genetics and disease. Trends Biochem. Sci. 25, 555–560 (2000).

    Article  CAS  Google Scholar 

  10. Skuder, P. et al. A polymorphism in mitochondrial DNA associated with IQ? Intelligence 21, 1–11 (1995).

    Article  Google Scholar 

  11. Yonekawa, H. et al. Origins of laboratory mice deduced from restriction patterns of mitochondrial DNA. Differentiation 22, 222–226 (1982).

    Article  CAS  Google Scholar 

  12. Kaneda, H. et al. Elimination of parental mitochondrial DNA in intraspecific crosses during early mouse embryogenesis. Proc. Natl. Acad. Sci. USA 92, 4542–4546 (1995).

    Article  CAS  Google Scholar 

  13. Nagao, Y. et al. Decreased physical performance of congenic mice with mismatch between the nuclear and the mitochondrial genome. Genes Genet. Syst. 73, 21–27 (1998).

    Article  CAS  Google Scholar 

  14. Dillin, A. et al. Rates of behavior and aging specified by mitochondrial function during development. Science 298, 2398–2401 (2002).

    Article  CAS  Google Scholar 

  15. Hirai, K. et al. Mitochondrial abnormalities in Alzheimer's disease. J. Neurosci. 21, 3017–3023 (2001).

    Article  CAS  Google Scholar 

  16. Martin-Romero, F.J., Garcia-Martin, E. & Gutierrez-Merino, C. Inhibition of oxidative stress produced by plasma membrane NADH oxidase delays low-potassium-induced apoptosis of cerebellar granule cells. J. Neurochem. 82, 705–715 (2002)

    Article  CAS  Google Scholar 

  17. Chavis, P., Fagni, L., Lansman, J.B. & Bockaert, J. Functional coupling between ryanodine receptors and L-type calcium channels in neurons. Nature 382, 719–722 (1996).

    Article  CAS  Google Scholar 

  18. Carey, M.R. & Lisberger, S.G. Embarrassed but not depressed. Eye opening lessons from cerebellar learning. Neuron 36, 223–226 (2002).

    Article  Google Scholar 

  19. Busciglio, J. et al. Altered metabolism of the amyloid β precursor protein is associated with mitochondrial dysfunction in Down's syndrome. Neuron 33, 677–688 (2002).

    Article  CAS  Google Scholar 

  20. Johnson, K.R., Zheng, Q.Y., Bykhovskaya, Y., Spirina, O. & Fischel-Ghodsian, N. A nuclear-mitochondrial DNA interaction affecting hearing impairment in mice. Nat. Genet. 27, 191–194 (2001).

    Article  CAS  Google Scholar 

  21. Roubertoux, P.L et al. Vocalizations in newborn mice: genetic analysis. Behav. Genet. 26, 427–437 (1996).

    Article  CAS  Google Scholar 

  22. Carlier, M., Roubertoux, P. & Cohen-Salmon, Ch. Early development in mice: I genotype and post-natal maternal effects. Physiol. Behav. 80, 837–844 (1983).

    Article  Google Scholar 

  23. Le Roy, I. et al. Neuronal and behavioral differences between Mus musculus domesticus (C57L6/JBy) and Mus musculus castaneus (CAST/Ei). Behav. Brain Res. 95, 135–142 (1998).

    Article  CAS  Google Scholar 

  24. Sluyter F., Marican, C., Roubertoux, P.L. & Crusio, W.E. Radial maze learning in two inbred mouse strains and their reciprocal congenics for the non-pseudoautosomal region of the Y chromosome. Brain Res. 835, 68–73 (1999).

    Article  CAS  Google Scholar 

  25. Dulioust, E. et al. Long-term effects of embryo freezing in mice. Proc. Natl. Acad. Sci. USA 92, 589–593 (1995).

    Article  CAS  Google Scholar 

  26. File, S.E. & Wardill, A.G. The reliability of the hole-board apparatus. Psychopharmacologia 44, 47–51 (1975).

    Article  CAS  Google Scholar 

  27. Simiand, J., Keane, P.E. & Morre, M. The staircase test in mice: a simple and efficient procedure for primary screening of anxiolytic agents. Psychopharmacology 84, 48–53 (1984).

    Article  CAS  Google Scholar 

  28. Wahlsten, D., Colbourne, F. & Pleus, R. A robust, efficient and flexible method for staining myelinated axons in blocks of brain tissue. J. Neurosci. Methods 123, 207–214 (2003).

    Article  Google Scholar 

  29. SAS Institute. SAS/STAT User's Guide version 6 (SAS Institute, Cary, North Carolina, 1989).

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Acknowledgements

We thank H. Yonekawa for mtDNA primers. This work was supported by the Centre National de la Recherche Scientifique to Génétique, Neurogénétique, Comportement and to Institut des Neurosciences Physiologiques et Cognitives and by Institut National de la Santé et de la Recherche Médicale and Fondation Jérôme Lejeune. F.S. received a fellowship from the Fondation Fyssen and C.C. received financial support from Laboratoires Ipsen and from the association “Vaincre la mucoviscidose”.

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Correspondence to Pierre L Roubertoux.

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Roubertoux, P., Sluyter, F., Carlier, M. et al. Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice. Nat Genet 35, 65–69 (2003). https://doi.org/10.1038/ng1230

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