Mitochondrial control of cell death induced by hyperosmotic stress.
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-X(L) 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.
Criollo
Alfredo
A
Institut Gustave Roussy - 39 rue Camille Desmoulins, F-94805, Villejuif, France.
Galluzzi
Lorenzo
L
Maiuri
M Chiara
MC
Tasdemir
Ezgi
E
Lavandero
Sergio
S
Kroemer
Guido
G
D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000096:biosynthesis; D001483:Base Sequence; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009997:Osmotic Pressure; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D051033:Apoptosis Inducing Factor; C494826:BAX protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c