Bax and Bak promote apoptosis by modulating endoplasmic reticular and mitochondrial Ca2+ stores

Alterations in intracellular Ca2+ homeostasis and cytochrome c release from mitochondria have been implicated in the regulation of apoptosis, but the relationship between there events remains unclear. Here we report that enforced expression of either Bax or Bak via adenoviral gene delivery results in the accumulation of the proteins in the endoplasmic reticulum (ER) and mitochondria, resulting in early caspase-independent BCL-2-sensitive release of the ER Ca2+ pool and subsequent Ca2+ accumulation in mitochondria. The inhibition of ER-to-mitochondrial Ca2+ transport with a specific inhibitor of mitochondrial Ca2+ uptake attenuates cytochrome c release and downstream biochemical events associated with apoptosis. Bax and Bak also directly sensitize mitochondria to cytochrome c release induced by immediate emptying of ER Ca2+ pool. Our results demonstrate that the effects of the multidomain proapoptotic BCL-2 family members Bak and Bax involve direct effects on the endoplasmic reticular Ca2+ pool with subsequent sensitization of mitochondria to calcium-mediated fluxes and cytochrome c release. These effects modulate the kinetics of cytochrome c release and apoptosis.