Prohibitin depletion extends lifespan of a TORC2/SGK-1 mutant through autophagy and the mitochondrial UPR

Abstract

Mitochondrial prohibitins (PHB) are highly conserved proteins with a peculiar effecton lifespan. While PHB depletion shortens lifespan of wild-type animals, it enhanceslongevity of a plethora of metabolically compromised mutants, including target ofrapamycin complex 2 (TORC2) mutants sgk-1 and rict-1. Here, we show that sgk-1mutants have impaired mitochondrial homeostasis, lipogenesis and yolk formation,plausibly due to alterations in membrane lipid and sterol homeostasis. Remarkably, allthese features are suppressed by PHB depletion. Our analysis shows the requirementof SRBP1/SBP-1 for the lifespan extension of sgk-1 mutants and the further extensionconferred by PHB depletion. Moreover, although the mitochondrial unfolded proteinresponse (UPR mt ) and autophagy are induced in sgk-1 mutants and upon PHB deple-tion, they are dispensable for lifespan. However, the enhanced longevity caused byPHB depletion in sgk-1 mutants requires both, the UPR mt and autophagy, but not mi-tophagy. We hypothesize that UPR mt induction upon PHB depletion extends lifespanof sgk-1 mutants through autophagy and probably modulation of lipid metabolism.