Modulation of Autophagy by Calcium Signalosome in Human Disease

Autophagy is a catabolic process that is largely regulated by extracellular and intracellular signaling pathways that are central to cellular metabolism and growth. Mounting evidence has shown that ion channels and transporters are important for basal autophagy functioning and influence autophagy to handle stressful situations. Besides its role in cell proliferation and apoptosis, intracellular Ca²⁺ is widely recognized as a key regulator of autophagy, acting through the modulation of pathways such as the mechanistic target of rapamycin complex 1, calcium/calmodulin-dependent protein kinase kinase 2, and protein kinase C. Proper spatiotemporal Ca²⁺ availability, coupled with a controlled ionic flow among the extracellular milieu, storage compartments, and the cytosol, is critical in determining the role played by Ca²⁺ on autophagy and on cell fate. The crosstalk between Ca²⁺ and autophagy has a central role in cellular homeostasis and survival during several physiologic and pathologic conditions. Here we review the main findings concerning the mechanisms and roles of Ca²⁺-modulated autophagy, focusing on human disorders ranging from cancer to neurologic diseases and immunity. By identifying mechanisms, players, and pathways that either induce or suppress autophagy, new promising approaches for preventing and treating human disorders emerge, including those based on the modulation of Ca²⁺-mediated autophagy.