Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan

Genes (Basel). 2019 Jul 13;10(7):532. 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 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.

Keywords: Conplastic mouse strains; glucose metabolism; healthspan; lifespan; mice; mitochondrial DNA (mtDNA); mitochondrially encoded complex I; mt-Nd2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA, Mitochondrial
  • Diet, High-Fat
  • Female
  • Glucose Intolerance
  • Longevity / genetics*
  • Male
  • Maternal Inheritance*
  • Metabolic Networks and Pathways / genetics
  • Mice, Inbred C57BL
  • Mitochondrial Proteins / genetics*
  • Mutation
  • NADH Dehydrogenase / genetics*
  • Stress, Physiological
  • Tryptophan / metabolism


  • DNA, Mitochondrial
  • Mitochondrial Proteins
  • NADH dehydrogenase subunit 2, mouse
  • Tryptophan
  • NADH Dehydrogenase
  • ND5 protein, mouse