Fig. 10.

The core molecular mechanisms of lysosome-dependent cell death. Lysosome-dependent cell death is triggered by ROS or other stimuli. A surge of ROS is one of the main triggers of the increase in calcium, which can occur through hyperactivation of TRPM2 and calcium efflux from lysosomes, leading to LMP and the release of cathepsins into the cytosol. Cathepsins catalyze the formation of multiple substrates, including Bid and apoptotic proteins, and initiate caspase-dependent cell death. Lysosome-dependent cell death occurs through a process involving Ca²⁺⁻dependent ADCY1, followed by an increase in cAMP and ultimately the inhibition of lysosomal acid SMase. In addition, ER stress can induce an increase in cytosolic Ca²⁺. High cytosolic calcium stimulates the activation of calpain, leading to the degradation of lysosomal membrane proteins such as LAMP1/2, which causes lysosomes to rupture, resulting in lysosome-dependent cell death. Abbreviations: TRPM2, transient receptor potential melastatin 2; LMP, lysosomal membrane permeabilization; cAMP, cyclic adenosine monophosphate; ADCY1, adenylate cyclase 1; SMase, sphingomyelinase; ER, endoplasmic reticulum; LAMP1/2, lysosome-associated membrane protein 1/2; Bid, BH3-interacting domain death agonist