Lysosomal calcium and autophagy.

Lysosomal calcium is emerging as a modulator of autophagy and lysosomal compartment, an obligatory partner to complete the autophagic pathway. A variety of specific signals such as nutrient deprivation or oxidative stress can trigger lysosomal calcium-mediated nuclear translocation of the transcription factor EB (TFEB), a master regulator of global lysosomal function. Also, lysosomal calcium can promote the formation of autophagosome vesicles (AVs) by a mechanism that requires the production of the phosphoinositide PI3P by the VPS34 autophagic complex and the activation of the energy-sensing kinase AMPK. Additionally, lysosomal calcium plays a role in membrane fusion and fission events involved in cellular processes such as endocytic maturation, autophagosome-lysosome fusion, lysosomal exocytosis, and lysosomal reformation upon autophagy completion. Lysosomal calcium-dependent functions are defective in cellular and animal models of the non-selective cation channel TRPML1, whose mutations in humans cause the neurodegenerative lysosomal storage disease mucolipidosis type IV (MLIV). Lysosomal calcium is not only acting as a positive regulator of autophagy, but it is also responsible for turning-off this process through the reactivation of the mTOR kinase during prolonged starvation. More recently, it has been described the role of lysosomal calcium on an elegant sequence of intracellular signaling events such as membrane repair, lysophagy, and lysosomal biogenesis upon the induction of different grades of lysosomal membrane damage. Here, we will discuss these novel findings that re-define the importance of the lysosome and lysosomal calcium signaling at regulating cellular metabolism.