Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan.

Area of Science:

• Mitochondrial biology
• Genetics
• Aging research

Background:

• Mitochondrial complex I is crucial for energy production and implicated in aging.
• While nuclear and mitochondrial DNA encode its proteins, the functional impact of mitochondrial DNA variants is less understood.
• Previous studies on mitochondrial DNA mutations and lifespan were mainly in invertebrates.

Purpose of the Study:

• To investigate the functional consequences of a specific mutation in the mitochondrial DNA-encoded complex I gene, mt-Nd2, on lifespan and age-related phenotypes in mice.
• To determine if mutations in other mitochondrial DNA-encoded complex I genes have similar effects.

Main Methods:

• Generated a conplastic mouse strain with a homoplasmic mutation (m.4738C > A) in the mt-Nd2 gene.
• Compared lifespan and metabolic health (glucose intolerance) between mutant and control mice.
• Assessed phenotypes in mice with a mutation in another complex I gene, mt-Nd5.

Main Results:

• Mice with the mt-Nd2 mutation exhibited a significantly shorter lifespan compared to controls.
• The mt-Nd2 mutation increased susceptibility to diet-induced glucose intolerance.
• Similar phenotypes were not observed in mice with an mt-Nd5 mutation.

Conclusions:

• A homoplasmic mutation in the mitochondrial gene mt-Nd2 modulates lifespan and glucose metabolism in mice.
• Altered cellular tryptophan levels are a potential mechanism linking the mutation to aging pathways.
• These findings underscore the functional relevance of specific mitochondrial DNA mutations in complex I for aging and age-related diseases.