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

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 consequence...

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Published in:Scientific reports 2018-04, Vol.8 (1), p.5872-15, Article 5872
Main Authors: Hirose, Misa, Schilf, Paul, Gupta, Yask, Zarse, Kim, Künstner, Axel, Fähnrich, Anke, Busch, Hauke, Yin, Junping, Wright, Marvin N., Ziegler, Andreas, Vallier, Marie, Belheouane, Meriem, Baines, John F, Tautz, Diethard, Johann, Kornelia, Oelkrug, Rebecca, Mittag, Jens, Lehnert, Hendrik, Othman, Alaa, Jöhren, Olaf, Schwaninger, Markus, Prehn, Cornelia, Adamski, Jerzy, Shima, Kensuke, Rupp, Jan, Häsler, Robert, Fuellen, Georg, Köhling, Rüdiger, Ristow, Michael, Ibrahim, Saleh M.
Format: Article
Language:English
Subjects:
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Coexistence
Deoxyribonucleic acid
DNA
DNA biosynthesis
Genomes
Glucose metabolism
Heteroplasmy
Humanities and Social Sciences
Life span
Metabolic pathways
Metabolism
Mitochondrial DNA
multidisciplinary
Mutation
Replication origins
Science
Science (multidisciplinary)
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Summary: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-mt AKR ) 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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-24290-6