Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan

• Published in: Genes 2019-07, Vol.10 (7), p.532
• Main Authors: Hirose, Misa, Schilf, Paul, Zarse, Kim, Busch, Hauke, Fuellen, Georg, Jöhren, Olaf, Köhling, Rüdiger, König, Inke R, Richer, Barbara, Rupp, Jan, Schwaninger, Markus, Seeger, Karsten, Sina, Christian, Ristow, Michael, Ibrahim, Saleh M
• Format: Article
• Language: English
• Subjects: Age groups; Aging; Alzheimer's disease; Animals; Dehydrogenases; Diet, High-Fat; DNA, Mitochondrial; Electron transport chain; Enzymes; Female; Females; Genes; Genomes; Glucose Intolerance; Glucose tolerance; High fat diet; Intolerance; Invertebrates; Life span; Longevity - genetics; Male; Males; Maternal Inheritance; Metabolic Networks and Pathways - genetics; Mice, Inbred C57BL; Mitochondrial DNA; Mitochondrial Proteins - genetics; Mutation; NADH Dehydrogenase - genetics; NADH-ubiquinone oxidoreductase; Oldest old people; Oxidative phosphorylation; Parkinson's disease; Phenotypes; Phosphorylation; Proteins; Stress, Physiological; Tryptophan; Tryptophan - metabolism; Vagina; Variance analysis; Worms
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes10070532

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 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 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, , suggesting the functional relevance of particular mutations in complex I to ageing and age-related diseases.