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.
Murphy
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AN
MitoKor, San Diego, CA 92121, USA.
Fiskum
G
G
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*
D019253:Proto-Oncogene Proteins c-bcl-2; D002118:Calcium