Role of SERCA1 truncated isoform in the proapoptotic calcium transfer from ER to mitochondria during ER stress.
Among the new players at the endoplasmic reticulum (ER)-mitochondria interface regulating interorganelle calcium signaling, those specifically involved during ER stress are not known at present. We report here that the truncated variant of the sarcoendoplasmic reticulum Ca(2+)-ATPase 1 (S1T) amplifies ER stress through the PERK-eIF2alpha-ATF4-CHOP pathway. S1T, which is localized in the ER-mitochondria microdomains, determines ER Ca(2+) depletion due to increased Ca(2+) leak, an increased number of ER-mitochondria contact sites, and inhibition of mitochondria movements. This leads to increased Ca(2+) transfer to mitochondria in both resting and stimulated conditions and activation of the mitochondrial apoptotic pathway. Interestingly, S1T knockdown was shown to prevent ER stress, mitochondrial Ca(2+) overload, and subsequent apoptosis. Thus, by bridging ER stress to apoptosis through increased ER-mitochondria Ca(2+) transfer, S1T acts as an essential determinant of cellular fate.
Chami
Mounia
M
INSERM U 807, Paris F-75015, France. mounia.chami@inserm.fr
Oulès
Bénédicte
B
Szabadkai
György
G
Tacine
Rachida
R
Rizzuto
Rosario
R
Paterlini-Bréchot
Patrizia
P
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D020126:Brefeldin A / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure; D004790:Enzyme Induction / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006367:HeLa Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000201:enzymology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020218:Response Elements / Q000235:genetics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000096:biosynthesis / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism
D051701:Activating Transcription Factor 4; D020126:Brefeldin A; D002118:Calcium; D015852:Eukaryotic Initiation Factor-2; D007527:Isoenzymes; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019892:eIF-2 Kinase; C506943:ATP2A1 protein, human