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

Open access
Date
2018Type
- Journal Article
Citations
Cited 18 times in
Web of Science
Cited 18 times in
Scopus
ETH Bibliography
yes
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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. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000229035Publication status
publishedExternal links
Journal / series
Scientific ReportsVolume
Pages / Article No.
Publisher
Nature Publishing GroupOrganisational unit
02540 - Institut für Translationale Medizin / Institute of Translational Medicine02070 - Dep. Gesundheitswiss. und Technologie / Dep. of Health Sciences and Technology
03976 - Ristow, Michael / Ristow, Michael
Funding
156031 - Molekulare Charakterisierung neuer Spezies-unabhängiger Regulatoren systemischer Alterung (SNF)
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Show all metadata
Citations
Cited 18 times in
Web of Science
Cited 18 times in
Scopus
ETH Bibliography
yes
Altmetrics