The manipulation of mitochondrial activity profoundly affects the lifespan of diverse organisms and mitochondria play a prominent role in age-associated human disorders. However, the cellular mechanisms regulating mitochondrial activity and the molecular basis of mitochondrial dysfunction in ageing are poorly understood. To date, there is no clear mechanistic explanation for the observed increased longevity of mitochondrial mutants.
The most relevant genetic pathway regulating ageing is the insulin/IGF-1 signalling (IIS) pathway. It is generally believed that mitochondrial dysfunctions exert its effect on lifespan independently of the IIS pathway. However, the mitochondrial prohibitin (PHB) complex influences cellular metabolism and mitochondrial biogenesis, affecting ageing in opposite ways in wild-type animals and IIS-defective C. elegans mutants. The striking opposite effect of prohibitin on longevity under different conditions offers a unique opportunity to understand how mitochondrial function relates with the cellular signalling status to regulate longevity.