Mitochondrial control of cell death induced by hyperosmotic stress |
| |
Authors: | Alfredo Criollo M. Chiara Maiuri Ezgi Tasdemir Sergio Lavandero Guido Kroemer |
| |
Affiliation: | (1) Institut Gustave Roussy - 39 rue Camille Desmoulins, F-94805 Villejuif, France;(2) INSERM, Unit “Apoptosis, Cancer and Immunity” - 39 rue Camille Desmoulins, F-94805 Villejuif, France;(3) Faculté de Médecine, Université Paris-Sud XI - 39 rue Camille Desmoulins, F-94805 Villejuif, France;(4) Department of Biochemistry and Molecular Biology, Faculty of Chemical and Pharmaceutical Sciences, FONDAP Center for Molecular Studies of the Cell, University of Chile, Olivos 1007, Santiago, 8380492, Chile |
| |
Abstract: | HeLa and HCT116 cells respond differentially to sorbitol, an osmolyte able to induce hypertonic stress. In these models, sorbitol promoted the phenotypic manifestations of early apoptosis followed by complete loss of viability in a time-, dose-, and cell type-specific fashion, by eliciting distinct yet partially overlapping molecular pathways. In HCT116 but not in HeLa cells, sorbitol caused the mitochondrial release of the caspase-independent death effector AIF, whereas in both cell lines cytochrome c was retained in mitochondria. Despite cytochrome c retention, HeLa cells exhibited the progressive activation of caspase-3, presumably due to the prior activation of caspase-8. Accordingly, caspase inhibition prevented sorbitol-induced killing in HeLa, but only partially in HCT116 cells. Both the knock-out of Bax in HCT116 cells and the knock-down of Bax in A549 cells by RNA interference reduced the AIF release and/or the mitochondrial alterations. While the knock-down of Bcl-2/Bcl-XL sensitized to sorbitol-induced killing, overexpression of a Bcl-2 variant that specifically localizes to mitochondria (but not of the wild-type nor of a endoplasmic reticulum-targeted form) strongly inhibited sorbitol effects. Thus, hyperosmotic stress kills cells by triggering different molecular pathways, which converge at mitochondria where pro- and anti-apoptotic members of the Bcl-2 family exert their control. A. Criollo and L. Galluzzi contributed equally to this work. |
| |
Keywords: | Apoptosis Bax Bcl-2 Hyperosmotic stress Mitochondria Sorbitol |
本文献已被 PubMed SpringerLink 等数据库收录! |
|