SIGNALING MECHANISMS AND OXIDATIVE STRESS IN APOPTOSIS

A variety of stimuli can induce cells to undergo apoptotic death. One of the most reproducible inducers is mild oxidative stress, be it via exposure to hydrogen peroxide, redox-cycling quinones or thiol-alkylat ing agents. Oxidative modifications of proteins and lipids have also b een observed in cells undergoing apoptosis in response to non-oxidativ e stimuli such as glucocorticoids or topoisomerase II inhibitors. This suggests that some unidentified oxidative changes occur during apopto sis in many, if not all, cases. However, recent experiments demonstrat ing apparently normal apoptosis even when cells are cultured at low ox ygen tensions show that reactive oxygen species cannot be essential me diators of this type of cell death. Experiments revealing that apoptos is is typically accompanied by a depletion of intracellular reduced gl utathione (GSH) are also discussed. As GSH depletion will lower a cell 's capacity to buffer against endogenous oxidants, we propose that it contributes to the increased oxidative damage commonly observed to acc ompany apoptosis. In addition, it may set a time limit on continued mi tochondrial function (and thus indirectly on total ATP levels and memb rane integrity) in apoptotic cells, and thereby explain the often obse rved 'secondary necrosis' of cells undergoing apoptosis in vitro.