Synergistic movements of Ca2+ and Bax in cells undergoing apoptosis

Apoptosis is a physiological counterbalance to mitosis and plays important roles in tissue development and homeostasis. Cytosolic Ca2+ has been implicated as a proapoptotic second messenger involved in both triggering apoptosis and regulating cell death-specific enzymes. A critical early event in apoptosis is associated with the redistribution of Bax from cytosol to mitochondria and endoplasmic reticulum (ER) membranes; however, the molecular mechanism of Bax translocation and its relationship to Ca2+ is largely unknown. Here we provide functional evidence for a synergistic interaction between the movements of intracellular Ca2+ and cytosolic Bax in the induction of apoptosis. Overexpression of Bax in cultured cells causes a loss of ER Ca2+ content. Depletion of ER Ca2+ through activation of the ryanodine receptor enhances the participation of Bax into the mitochondrial membrane. Neither Bax translocation nor Bax-induced apoptosis is affected by buffering of cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)-ethane-N,N N ' ,N ' -tetraacetic acid, suggesting that depletion of ER Ca2+ rather than elevation of cytosolic Ca2+ is the signal for cell apoptosis. This dynamic interplay of Ca2+ and Bax movements may serve as an amplifying factor in the initial signaling steps of apoptosis.