Oxidant-induced apoptosis: a consequence of lethal lysosomal leak?

Area of Science:

• Cell Biology
• Biochemistry
• Toxicology

Background:

• Oxidative stress is implicated in cellular damage and death pathways.
• Lysosomes play a critical role in cellular degradation and homeostasis.
• Iron's role in oxidative reactions within cells is increasingly recognized.

Purpose of the Study:

• To investigate the role of lysosomal integrity and iron in oxidative stress-induced apoptosis.
• To elucidate the mechanism by which oxidative stress triggers cell death in macrophages.
• To determine the impact of iron chelation and loading on oxidative stress-induced apoptosis.

Main Methods:

• Macrophage-like J-774 cells were exposed to varying levels of oxidative stress (hydrogen peroxide).
• Lysosomal integrity was assessed using the acridine orange relocalization test.
• Cellular iron levels were modulated using desferrioxamine (chelation) and ferric iron (loading).
• Cathepsin-D release into the cytosol was monitored as an indicator of lysosomal enzyme leakage.

Main Results:

• Limited oxidative stress induced lysosomal rupture and apoptosis, characterized by cathepsin-D release.
• Severe oxidative stress led to extensive lysosomal rupture and necrosis.
• Chelation of intralysosomal iron with desferrioxamine largely prevented oxidative stress-induced apoptosis.
• Endocytotic uptake of ferric iron enhanced oxidative stress-induced apoptosis.

Conclusions:

• Oxidant-mediated and iron-catalyzed lysosomal rupture initiates apoptosis.
• Decompartmentalization of lysosomal enzymes due to rupture promotes apoptotic processes.
• Intralysosomal iron is a critical mediator in oxidative stress-induced lysosomal damage and subsequent apoptosis.