Bcl-2 and Ca(2+)-mediated mitochondrial dysfunction in neural cell death.

Although altered Ca2+ homoeostasis is believed to be a primary cause of death for many cell types in response to toxic insults, the specific Ca(2+)-stimulated event responsible for directing cells down the death pathway has remained elusive. Recent publications support the hypothesis that mitochondrial Ca2+ sequestration is the critical event in induction of excitotoxic neuronal death. If similar pathways are involved in the induction of Ca(2+)-induced necrotic and apoptotic death, then agents that mimic the action of the anti-apoptotic protein Bcl-2 should be particularly useful. Our previous results provide evidence that Bcl-2 increases the maximal capacity of mitochondria to accumulate Ca2+ while providing resistance to Ca(2+)-induced respiratory damage. In addition, we have found that Bcl-2 can block Ca(2+)-ionophore-induced delayed cell death. These data predict that in response to a challenging mitochondrial Ca2+ load, Bcl-2-containing mitochondria would be capable of continuing bioenergetic function, potentially avoiding a catastrophic death signalling event.