Regulation of endoplasmic reticulum Ca2+ dynamics by proapoptotic BCL-2 family members

Uncontrolled cytosolic Ca2+ overload is a common cause of cell death in several pathological conditions. Recent evidences reveal a more regulated role for intracellular Ca2+ stores in controlling cell death. Proteins of the BCL-2 family include anti- and proapoptotic members that control the mitochondrial amplification loop of apoptosis. The antiapoptotic protein BCL-2 prevents this mitochondrial loop, while the " multidomain" proapoptotic proteins BAX and BAK are crucial to initiate it. BCL-2, BAX and BAK localize also to the endoplasmic reticulum (ER), the main intracellular Ca2+ store. Overexpression of BCL-2 reduces resting ER Ca2+ and death in response to apoptotic stimuli that mobilize Ca 2+. Our recent data indicate that multidomain proapoptotics also influence Ca2+ metabolism. Cells deficient for Bax, Bak (DKO) display lowered steady state ER Ca2+ concentrations ([Ca 2+]er) and secondarily decreased mitochondrial Ca 2+ uptake. Genetic and pharmacologic correction of [Ca 2+]er indicates that it controls death in response to Ca2+-dependent, mitochondria utilizing signals such as oxidative stress and lipid mediators; and that it participates in the regulation of the apoptotic response to most intrinsic stimuli, such as staurosporine. Thus, BAX and BAK control apoptosis not only at the mitochondria, but also at the ER, an obligate checkpoint for Ca2+-dependent apoptotic stimuli. © 2003 Elsevier Inc. All rights reserved.