Redox activity within the lysosomal compartment: implications for aging and apoptosis

Abstract

The lysosome is a redox-active compartment containing low-mass iron and copper liberated by autophagic degradation of metalloproteins. The acidic milieu and high concentration of thiols within lysosomes will keep iron in a reduced (ferrous) state, which can react with endogenous or exogenous hydrogen peroxide. Consequent intralysosomal Fenton reactions may give rise to the formation of lipofuscin or "age pigment" that accumulates in long-lived postmitotic cells that cannot dilute it by division. Extensive accumulation of lipofuscin seems to hinder normal autophagy and may be an important factor behind aging and age-related pathologies. Enhanced oxidative stress causes lysosomal membrane permeabilization, with ensuing relocation to the cytosol of iron and lysosomal hydrolytic enzymes, with resulting apoptosis or necrosis. Lysosomal copper is normally not redox active because it will form non-redox-active complexes with various thiols. However, if cells are exposed to lysosomotropic chelators that do not bind all the copper coordinates, highly redox-active complexes may form, with ensuing extensive lysosomal Fenton-type reactions and loss of lysosomal stability. Because many malignancies seem to have increased amounts of copper-containing macromolecules that are turned over by autophagy, it is conceivable that lysosomotropic copper chelators may be used in the future in ROS-based anticancer therapies.