Aging is a complex and multifactorial process influenced by different pathways interacting in a not completely defined manner. Mitochondrial prohibitins (PHBs) are strongly evolutionarily conserved proteins with a peculiar effect on lifespan. While their depletion shortens lifespan of wild type animals, it enhances longevity of a plethora of metabolically compromised mutants, including target of rapamycin complex 2 (TORC2) mutants sgk-1 and rict-1. Intriguingly, TORC2 mutants induce the mitochondrial unfolded protein response (UPRmt), while reducing the strong UPRmt elicited by PHB depletion. To understand this inverse correlation between lifespan and activation of the UPRmt, we studied the interaction of TORC2 signaling with mitochondrial quality control mechanisms including mitophagy, the UPRmt and autophagy. Our data revealed that sgk-1 mutants have increased mitochondrial size, respiration rate and ROS production, phenotypes suppressed by PHB depletion. A transcription factor RNAi screen identified lipid and sterol homeostasis as UPRmt modulators in sgk-1 mutants. In accordance, sgk-1(ok538) show impaired lipogenesis, yolk formation and autophagy flux, plausibly due to altered organelle contacts. Remarkably, all these features are suppressed by PHB depletion. Lifespan analysis showed that autophagy and the UPRmt, but not mitophagy, are required for the enhanced longevity caused by PHB depletion in sgk-1 mutants. Because the UPRmt transcription factor ATFS-1 activates autophagy, we hypothesize that UPRmt induction upon PHB depletion extends lifespan of sgk-1 mutants through autophagy. Our results strongly suggest that PHB depletion suppresses the autophagy defects of sgk-1 mutants by altering membrane lipid composition at ER-mitochondria contact sites, where TORC2 localizes.

Trabajo presentado en Virtual European Worm Meeting, celebrado en modalidad virtual del 22 al 23 de junio de 2020.