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


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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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).

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