Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan
Abstract
Mitochondrial complex I—the largest enzyme complex of the mitochondrial oxidative phosphorylation machinery—has been proposed to contribute to a variety of age-related pathological alterations as well as longevity. The enzyme complex-consisting proteins are encoded by both nuclear (nDNA) and mitochondrial DNA (mtDNA). While some association studies of mtDNA encoded complex I genes and lifespan in humans have been reported, experimental evidence and the functional consequence of such variants is limited to studies using invertebrate models. Here, we present experimental evidence that a homoplasmic mutation in the mitochondrially encoded complex I gene mt-Nd2 modulates lifespan by altering cellular tryptophan levels and, consequently, ageing-related pathways in mice. A conplastic mouse strain carrying a mutation at m.4738C > A in mt-Nd2 lived slightly, but significantly, shorter than the controls did. The same mutation led to a higher susceptibility to glucose intolerance induced by high-fat diet feeding. These phenotypes were not observed in mice carrying a mutation in another mtDNA encoded complex I gene, mt-Nd5, suggesting the functional relevance of particular mutations in complex I to ageing and age-related diseases. Mehr anzeigen
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https://doi.org/10.3929/ethz-b-000358948Publikationsstatus
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MDPIThema
Conplastic mouse strains; mitochondrially encoded complex I; mitochondrial DNA (mtDNA); lifespan; mt-Nd2; healthspan; glucose metabolism; miceOrganisationseinheit
03976 - Ristow, Michael (ehemalig) / Ristow, Michael (former)
Förderung
156031 - Molekulare Charakterisierung neuer Spezies-unabhängiger Regulatoren systemischer Alterung (SNF)