Mitochondria as targets of neuroprotection by Bcl-2 family proteins

Neural cell death that accompanies cerebral ischemia/reperfusion is mediated in part by mitochondrial alterations caused by elevated intracellular Ca2+, oxidative stress, and redistribution or activation of pro-apoptotic proteins, e.g., Bar and Bid. Bcl-2 is membrane protein localized primarily to mitochondria that protects against ischemic brain injury, hypoxic neural cell death, oxidative stress, and mitochondrial respiratory dysfunction caused by exposure to elevated Ca2+. Bcl-2 also protects against the release of cytochrome c and other pro-apoptotic mitochondrial proteins evoked by either Ca2+ or by peptides that contain a BH3 cell death domain. This report summarizes experiments performed with permeabilized cells where mitochondrial cytochrome c release and mitochondrial membrane potential were monitored in response to the addition of either Ca2+ plus pro-oxidants, e.g., t-butyl hydroperoxide, or a synthetic peptide containing the BH3 domain of Bar. The results support the hypotheses that: 1. Bcl-2 inhibits the Ca2+-stimulated mitochondrial permeability transition and associated cytochrome c release by increasing mitochondrial resistance to pyridine nucleotide oxidation and; 2. Bcl-2 inhibits cytochrome c release elicited by the Bax-BH3 peptide by a different mechanism that is independent of the mitochondrial pyridine nucleotide redox state.