PT  - JOURNAL ARTICLE
AU  - Misa Hirose
AU  - Paul Schilf
AU  - Kim Zarse
AU  - Hauke Busch
AU  - Georg Füllen
AU  - Olaf Jöhren
AU  - Rüdiger Köhling
AU  - Inke R König
AU  - Barbara Richer
AU  - Jan Rupp
AU  - Markus Schwaninger
AU  - Karsten Seeger
AU  - Christian Sina
AU  - Michael Ristow
AU  - Saleh M Ibrahim
TI  - Maternally inherited differences within mitochondrial Complex I control murine healthspan
AID  - 10.1101/472092
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 472092
4099  - http://biorxiv.org/content/early/2018/11/16/472092.short
4100  - http://biorxiv.org/content/early/2018/11/16/472092.full
AB  - 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 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.