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Título: | Prohibitin-mediated lifespan and mitochondrial stress implicate SGK-1, insulin/IGF and mTORC2 in C. elegans |
Autor: | Gatsi, Roxani CSIC ORCID; Schulze, Bettina; Rodríguez-Palero, María Jesús CSIC ORCID; Hernando-Rodríguez, Blanca CSIC ORCID; Baumeister, Ralf; Artal-Sanz, Marta CSIC ORCID | Fecha de publicación: | 2014 | Editor: | Public Library of Science | Citación: | PLoS ONE 9(9): e107671 (2014) | Resumen: | Lifespan regulation by mitochondrial proteins has been well described, however, the mechanism of this regulation is not fully understood. Amongst the mitochondrial proteins profoundly affecting ageing are prohibitins (PHB-1 and PHB-2). Paradoxically, in C. elegans prohibitin depletion shortens the lifespan of wild type animals while dramatically extending that of metabolically compromised animals, such as daf-2-insulin-receptor mutants. Here we show that amongst the three kinases known to act downstream of daf-2, only loss of function of sgk-1 recapitulates the ageing phenotype observed in daf-2 mutants upon prohibitin depletion. Interestingly, signalling through SGK-1 receives input from an additional pathway, parallel to DAF-2, for the prohibitin-mediated lifespan phenotype. We investigated the effect of prohibitin depletion on the mitochondrial unfolded protein response (UPRmt). Remarkably, the lifespan extension upon prohibitin elimination, of both daf-2 and sgk-1 mutants, is accompanied by suppression of the UPRmtinduced by lack of prohibitin. On the contrary, gain of function of SGK-1 results in further shortening of lifespan and a further increase of the UPRmtin prohibitin depleted animals. Moreover, SGK-1 interacts with RICT-1 for the regulation of the UPRmtin a parallel pathway to DAF-2. Interestingly, prohibitin depletion in rict-1 loss of function mutant animals also causes lifespan extension. Finally, we reveal an unprecedented role for mTORC2-SGK-1 in the regulation of mitochodrial homeostasis. Together, these results give further insight into the mechanism of lifespan regulation by mitochondrial function and reveal a cross-talk of mitochondria with two key pathways, Insulin/IGF and mTORC2, for the regulation of ageing and stress response. | Descripción: | This is an open-access article distributed under the terms of the Creative Commons Attribution License. | Versión del editor: | http://dx.doi.org/10.1371/journal.pone.0107671 | URI: | http://hdl.handle.net/10261/129428 | DOI: | 10.1371/journal.pone.0107671 | Identificadores: | doi: 10.1371/journal.pone.0107671 issn: 1932-6203 |
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