When lipid homeostasis runs havoc: Lipotoxicity links lysosomal dysfunction to autophagy

Autophagy is one of the major cellular degradation pathways, which prevents accumulation of cellular wastes including "hazardous" material such as oxidized proteins and lipids and allows removal of aggregates and dysfunctional organelles. Hence, autophagy is meant to preserve cell survival, and is mostly protective. However, autophagy may trigger a feedforward, exaggerated cycle in which cells continue to degrade proteins and organelles, finally leading to autophagy-dependent cell death (ADCD), a process that can be initiated with lysosomotropic detergents, which are protonated within the lysosome and cause a permeabilization of the membrane. Such drugs may be useful to combat cancer. In some paradigms of ADCD, there is evidence that the cellular fate is determined by the integrity of lysosomal membranes, transporters, enzymes and ion gradients. Detergent-like effects of lysosomotropic drugs can over-activate autophagy. A disruption of the lysosomal membrane barrier with leakage of lysosomal enzymes or lipids may trigger a vicious cycle via proteases and accumulation of lipids, which impair the functions of the plasma - and organelle membranes. This review summarizes the current evidence for a crosstalk between lysosomal dysfunction and autophagy and the lysosomal events, which progress toward ADCD with a focus on the role of sphingolipids and cholesterol as cargo and as regulators of ADCD.