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 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.