OXIDANT-INDUCED APOPTOSIS - A CONSEQUENCE OF LETHAL LYSOSOMAL LEAK

When macrophage-like J-774 cells are subjected to limited oxidative st ress, such as exposure to hydrogen peroxide in a moderate bolus dose, some of their lysosomes rupture - as here assayed by the acridine oran ge relocalization test - secondary to intralysosomal, iron-catalysed, oxidative reactions. The resultant leakage into the cytosol of hydroly tic enzymes, such as cathepsin-D (as shown here), may initiate a slow degradation/fragmentation process of an apoptotic type within cells st ill having intact plasma membranes. In contrast, severe oxidative stre ss also results in extensive lysosomal rupture but leads to necrosis. The chelation of (normally occurring) intralysosomal low-molecular wei ght iron, by endocytotic uptake of desferrioxamine, largely prevents o xidative stress-induced apoptosis whereas lysosomal iron-loading, by e ndocytotic uptake of complexed ferric iron, considerably enhances the process. We conclude that oxidant-mediated and iron-catalysed lysosoma l rupture leads to decompartmentalization of lysosomal enzymes which i n turn may initiate and promote the apoptotic process.