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Journal Article

Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice

MPS-Authors
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Yin,  Junping
Guest Group Evolutionary Genomics, Max Planck Institute for Evolutionary Biology, Max Planck Society;

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Vallier,  Marie
Guest Group Evolutionary Genomics, Max Planck Institute for Evolutionary Biology, Max Planck Society;

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Belheouane,  Meriem
Guest Group Evolutionary Genomics, Max Planck Institute for Evolutionary Biology, Max Planck Society;

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Baines,  John F.
Guest Group Evolutionary Genomics, Max Planck Institute for Evolutionary Biology, Max Planck Society;

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Tautz,  Diethard
Department Evolutionary Genetics, Max Planck Institute for Evolutionary Biology, Max Planck Society;

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s41598-018-24290-6.pdf
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Citation

Hirose, M., Schilf, P., Gupta, Y., Zarse, K., Künstner, A., Fähnrich, A., et al. (2018). Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice. Scientific Reports, 8(1): 5872. doi:10.1038/s41598-018-24290-6.


Cite as: http://hdl.handle.net/21.11116/0000-0001-9BFD-4
Abstract
Mutations in mitochondrial DNA (mtDNA) lead to heteroplasmy, i.e., the intracellular coexistence of wild-type and mutant mtDNA strands, which impact a wide spectrum of diseases but also physiological processes, including endurance exercise performance in athletes. However, the phenotypic consequences of limited levels of naturally arising heteroplasmy have not been experimentally studied to date. We hence generated a conplastic mouse strain carrying the mitochondrial genome of an AKR/J mouse strain (B6-mtAKR) in a C57BL/6 J nuclear genomic background, leading to >20% heteroplasmy in the origin of light-strand DNA replication (OriL). These conplastic mice demonstrate a shorter lifespan as well as dysregulation of multiple metabolic pathways, culminating in impaired glucose metabolism, compared to that of wild-type C57BL/6 J mice carrying lower levels of heteroplasmy. Our results indicate that physiologically relevant differences in mtDNA heteroplasmy levels at a single, functionally important site impair the metabolic health and lifespan in mice.