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Trabajo presentado en Virtual European Worm Meeting, celebrado en modalidad virtual del 22 al 23 de junio de 2020., 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 EMBO Workshop C. elegans development, cell biology and gene expression and European Worm Meeting, celebrado en Barcelona (España) del 13 al 17 de junio de 2018.

Resumen del trabajo presentado al 4th Spanish Worm Meeting, celebrado en Carmona (Sevilla) del 14 al 15 de marzo de 2013., Prohibitins are ubiquitous, evolutionarily strongly conserved proteins that localize in mitochondria. Prohibitin depletion shortens life span in wild type worms while, in contrast, in metabolically challenged animals prohibitin depletion promotes life span. We focus on the interactions of prohibitins with the Insulin/IGF-1-like signaling pathway. Mutations in the insulin receptor daf-2 result in strong lifespan extension and probibitin depletion dramatically enhances this phenotype (Artal-Sanz and Tavernarakis, 2009). In order to understand better this opposing effect of prohibitins on lifespan, we looked at genes involved in insulin signalling downstream of daf-2. Interestingly, the only component we identified in the pathway to interact with prohibitins is the sgk-1 gene. Similar to daf-2, depletion of prohibitins in the absence of sgk-1 extends life span. SGK-1 is a serine/threonine protein kinase that is orthologous to the mammalian serumand glucocorticoid-inducible kinases (SGKs) and it acts in parallel to the AKT kinases to mediate DAF-2 signaling for the control of development, stress response, and longevity (Hertweck et al, 2004). Various sources of evidence (Soukas et al, 2009; Jones et al, 2009) have suggested that sgk-1 acts as a receiver of information coming from the Rictor/TORC2 pathway, which is implicated in sensing of the nutrient status of C. elegans, and this information can be further processed to regulate life span. Data on the interaction of prohibitins with SGK-1 in the regulation of lifespan will be discussed.