title: Prohibitin-mediated lifespan and mitochondrial stress implicate SGK-1, insulin/IGF and mTORC2 in C. elegans.
abstract: 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 UPRmt induced 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 UPRmt in prohibitin depleted animals. Moreover, SGK-1 interacts with RICT-1 for the regulation of the UPRmt in 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.
authors.affiliation: CABD, Centro Andaluz de Biología del Desarrollo, CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Sevilla, Spain.
authors.forename: Roxani
authors.initials: R
authors.lastname: Gatsi
authors.affiliation: Centre for Biological Signalling Studies (BIOSS), Albert-Ludwigs-University of Freiburg, Freiburg, Germany; Laboratory for Bioinformatics and Molecular Genetics, Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Schulze
authors.affiliation: CABD, Centro Andaluz de Biología del Desarrollo, CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Sevilla, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Rodríguez-Palero
authors.affiliation: CABD, Centro Andaluz de Biología del Desarrollo, CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Sevilla, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Hernando-Rodríguez
authors.affiliation: Centre for Biological Signalling Studies (BIOSS), Albert-Ludwigs-University of Freiburg, Freiburg, Germany; Laboratory for Bioinformatics and Molecular Genetics, Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany; Center for Biochemistry and Molecular Cell Research, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Baumeister
authors.affiliation: CABD, Centro Andaluz de Biología del Desarrollo, CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Sevilla, Spain; Centre for Biological Signalling Studies (BIOSS), Albert-Ludwigs-University of Freiburg, Freiburg, Germany; Laboratory for Bioinformatics and Molecular Genetics, Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Artal-Sanz
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008017:Life Expectancy; D000076225:Mechanistic Target of Rapamycin Complex 2; D008928:Mitochondria / Q000502:physiology*; D046912:Multiprotein Complexes / Q000378:metabolism*; D000091402:Prohibitins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012097:Repressor Proteins / Q000502:physiology*; D013002:Somatomedins / Q000378:metabolism*; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D007328:Insulin; D046912:Multiprotein Complexes; D000091402:Prohibitins; D012097:Repressor Proteins; D013002:Somatomedins; C000717335:phb-1 protein, C elegans; C000717338:prohibitin 2, C elegans; D000076225:Mechanistic Target of Rapamycin Complex 2; D017346:Protein Serine-Threonine Kinases; C540745:Sgk-1 protein, C elegans; D058570:TOR Serine-Threonine Kinases