BCL-2 POTENTIATES THE MAXIMAL CALCIUM-UPTAKE CAPACITY OF NEURAL CELL MITOCHONDRIA

Expression of the human protooncogene bcl-2 protects neural cells from death induced by many forms of stress, including conditions that grea tly elevate intracellular Ca2+. Considering that Bcl-2 is partially lo calized to mitochondrial membranes and that excessive mitochondrial Ca 2+ uptake can impair electron transport and oxidative phosphorylation, the present study tested the hypothesis that mitochondria from Bcl-2- expressing cells have a higher capacity for energy-dependent Ca2+ upta ke and a greater resistance to Ca2+-induced respiratory injury than mi tochondria from cells that do not express this protein. The overexpres sion of bcl-2 enhanced the mitochondrial Ca2+ uptake capacity using ei ther digitonin-permeabilized GT1-7 neural cells or isolated GT1-7 mito chondria by 1.7 and 3.9 fold, respectively, when glutamate and malate were used as respiratory substrates. This difference was less apparent when respiration was driven by the oxidation of succinate in the pres ence of the respiratory complex I inhibitor rotenone. Mitochondria fro m Bcl-2 expressors were also much more resistant to inhibition of NADH -dependent respiration caused by sequestration of large Ca2+ loads. Th e enhanced ability of mitochondria within Bcl-2-expressing cells to se quester large quantities of Ca2+ without undergoing profound respirato ry impairment provides a plausible mechanism by which Bcl-2 inhibits c ertain forms of delayed cell death, including neuronal death associate d with ischemia and excitotoxicity.