Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C. elegans.
Marked alterations in cellular energy metabolism are a universal hallmark of the ageing process. The biogenesis and function of mitochondria, the energy-generating organelles in eukaryotic cells, are primary longevity determinants. Genetic or pharmacological manipulations of mitochondrial activity profoundly affect the lifespan of diverse organisms. However, the molecular mechanisms regulating mitochondrial biogenesis and energy metabolism during ageing are poorly understood. Prohibitins are ubiquitous, evolutionarily conserved proteins, which form a ring-like, high-molecular-mass complex at the inner membrane of mitochondria. Here, we show that the mitochondrial prohibitin complex promotes longevity by modulating mitochondrial function and fat metabolism in the nematode Caenorhabditis elegans. We found that prohibitin deficiency shortens the lifespan of otherwise wild-type animals. Notably, knockdown of prohibitin promotes longevity in diapause mutants or under conditions of dietary restriction. In addition, prohibitin deficiency extends the lifespan of animals with compromised mitochondrial function or fat metabolism. Depletion of prohibitin influences ATP levels, animal fat content and mitochondrial proliferation in a genetic-background- and age-specific manner. Together, these findings reveal a novel mechanism regulating mitochondrial biogenesis and function, with opposing effects on energy metabolism, fat utilization and ageing in C. elegans. Prohibitin may have a similar key role in modulating energy metabolism during ageing in mammals.
Artal-Sanz
Marta
M
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion 71110, Crete, Greece. martal@ibv.csic.es
Tavernarakis
Nektarios
N
D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins; D031204:Caloric Restriction; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D055785:Gene Knockdown Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D008136:Longevity / Q000235:genetics / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D009154:Mutation / Q000235:genetics; D000091402:Prohibitins; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D029742:Caenorhabditis elegans Proteins; D000091402:Prohibitins; D012097:Repressor Proteins; C000717338:prohibitin 2, C elegans; D000255:Adenosine Triphosphate