Autophagy – The liaison between the lysosomal system and cell death

Introduction The involvement of lysosomes, the organelle with the highest concentration of hydrolases, in cellular death has been extensively analyzed in different contexts in the past. In many of those studies, lysosomes were proposed to play a “ passive” role in the cellular death process, resulting from the leakage of potent lysosomal enzymes into the cytosol. In fact, rupture of the lysosomal membrane after various types of cellular injury or under certain pathological conditions can lead to both apoptotic and nonapoptotic cell death. For example, lysomotropic agents, certain lipid products such as sphingosine or ceramide, a wide variety of death stimuli such as death receptor activation, p53 activation, microtubule-stabilizing agents, oxidative stress, and growth factor deprivation induce lysosomal permeabilization and the release of lysosomal proteases, generically known as cathepsins, into the cytosol. Studies using both genetic and pharmacological blockage of cathepsins support that cytosolic release of these lysosomal hydrolases can mediate caspase-dependent and –independent cell death.