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 Ca²⁺-ATPase 1 (S1T) amplifies ER stress through the PERK-eIF2α-ATF4-CHOP pathway. S1T, which is localized in the ER-mitochondria microdomains, determines ER Ca²⁺ depletion due to increased Ca²⁺ leak, an increased number of ER-mitochondria contact sites, and inhibition of mitochondria movements. This leads to increased Ca²⁺ 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 Ca²⁺ overload, and subsequent apoptosis. Thus, by bridging ER stress to apoptosis through increased ER-mitochondria Ca²⁺ transfer, S1T acts as an essential determinant of cellular fate.