2024-03-28T12:41:20Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1294282021-12-28T16:26:45Zcom_10261_128com_10261_1col_10261_381
Prohibitin-mediated lifespan and mitochondrial stress implicate SGK-1, insulin/IGF and mTORC2 in C. elegans
Gatsi, Roxani
Schulze, Bettina
Rodríguez-Palero, María Jesús
Hernando-Rodríguez, Blanca
Baumeister, Ralf
Artal-Sanz, Marta
Ministerio de Economía y Competitividad (España)
German Research Foundation
European Research Council
European Commission
BIOSS Centre for Biological Signalling Studies (Germany)
This is an open-access article distributed under the terms of the Creative Commons Attribution License.
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.
2016-02-25T09:48:17Z
2016-02-25T09:48:17Z
2014
2016-02-25T09:48:18Z
artículo
PLoS ONE 9(9): e107671 (2014)
http://hdl.handle.net/10261/129428
10.1371/journal.pone.0107671
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100001659
http://dx.doi.org/10.13039/501100000781
http://dx.doi.org/10.13039/501100000780
25265021
eng
Publisher's version
http://dx.doi.org/10.1371/journal.pone.0107671
Sí
info:eu-repo/grantAgreement/EC/FP7/281691
http://creativecommons.org/licenses/by/4.0/
openAccess
Public Library of Science