BCL-2 FUNCTIONS IN AN ANTIOXIDANT PATHWAY TO PREVENT APOPTOSIS

Bcl-2 inhibits most types of apoptotic cell death, implying a common m echanism of lethality. Bcl-2 is localized to intracellular sites of ox ygen free radical generation including mitochondria, endoplasmic retic ula, and nuclear membranes. Antioxidants that scavenge peroxides, N-ac etylcysteine and glutathione peroxidase, countered apoptotic death, wh ile manganese superoxide dismutase did not. Bcl-2 protected cells from H2O2- and menadione-induced oxidative deaths. Bcl-2 did not prevent t he cyanide-resistant oxidative burst generated by menadione. Two model systems of apoptosis showed no increment in cyanide-resistant respira tion, and generation of endogenous peroxides continued at an inherent rate that was unaltered by Bcl-2. Following an apoptotic signal, cells sustained progressive lipid peroxidation. Overexpression of Bcl-2 fun ctioned suppress lipid peroxidation completely. We propose a model in which Bcl-2 regulates an antioxidant pathway at sites of free radical generation.