Differential effects of Bcl-2 on cell death triggered under ATP-depleting conditions

The intracellular ATP concentration decides on the onset of either apoptosi s or necrosis in Jurkat cells exposed to death stimuli. Bcl-2 can block apo ptotic demise, which occurs preferably under conditions of high cellular AT P levels. Here, we investigated the effects of Bcl-2 on the necrotic type o f cell demise that prevails under conditions of energy loss. ATP levels wer e modulated by using mitochondrial inhibitors, such as rotenone or S-nitros oglutathione, in medium either lacking glucose or supplemented with glucose to stimulate glycolytic ATP generation. Under conditions of ATP depletion, staurosporine (STS) induced >90% necrosis in vector control-transfected ce lls, whereas bcl-2-transfected cells were protected. Thus, the antiapoptoti c protein Bcl-2 can reduce the overall amount of cell death in ATP-depleted cells regardless whether it occurs by apoptosis or necrosis. Cytochrome c release, normally preceding STS-induced necrosis, was also inhibited by Bcl -2. However, Bcl-2 did not prevent an initial STS-induced drop of the mitoc hondrial membrane potential (Delta Psi (m)). Therefore, the mechanisms wher eby Bcl-2 prevents cell death and favors retention of cytochrome c in the m itochondria require neither the maintenance of mitochondrial Delta Psi nor the maintenance of normal ATP levels. (C) 2001 Academic Press.