Oxidative damage of lysosomes in regulated cell death systems: Pathophysiology and pharmacologic interventions

Lysosomes are small specialized organelles containing a variety of different hydrolase enzymes that are responsible for degradation of all macromolecules, entering the cells through the endosomal system or originated from the internal sources. This allows for transport and recycling of nutrients and internalization of surface proteins for antigen presentation as well as maintaining cellular homeostasis. Lysosomes are also important storage compartments for metal ions and nutrients. The integrity of lysosomal membrane is central to maintaining their normal function, but like other cellular membranes, lysosomal membrane is subject to damage mediated by reactive oxygen species. This results in spillage of lysosomal enzymes into the cytoplasm, leading to proteolytic damage to cellular systems and organelles. Several forms of lysosomal dependent cell death have been identified in diseases. Examination of these events are important for finding treatment strategies relevant to cancer or neurodegenerative diseases as well as autoimmune deficiencies. In this review, we have examined the current literature on involvement of lysosomes in induction of programed cell death and have provided an extensive list of therapeutic approaches that can modulate cell death. Exploitation of these mechanisms can lead to novel therapies for cancer and neurodegenerative diseases.