Cell Press, Molecular Cell, 5(32), p. 641-651, 2008
DOI: 10.1016/j.molcel.2008.11.014
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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-eIF2 alpha-ATF4-CHOP pathway. SlT, 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, SlT 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.