Fig. 2.

Ca²⁺ induces autophagy. The cytosolic calcium concentration can be elevated by multiple factors, including Ca²⁺-mobilizing agents, the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase (SERCA) inhibitors, or other autophagy inducers (such as starvation and rapamycin). These factors stimulate IP₃R-mediated Ca²⁺ release from the ER. Stimulus-induced Ca²⁺ release could be blunted by the Ca²⁺ chelator, BAPTA, or Bcl-2. Increased cytosolic Ca²⁺ can trigger autophagy through various mechanisms; the activation of CaMKKβ by Ca²⁺ stimulates the AMPK-mediated suppression of mTOR signaling. The overexpression of LRRK2 promotes Ca²⁺ release from lysosomal stores and then initiates autophagy through the Ca²⁺/CaMKKβ/AMPK pathway, but this effect is mTOR-independent. Ca²⁺-activated autophagy can also be AMPK-independent. PKCθ activation followed by elevated Ca²⁺ is required for ER stress-induced autophagy. Ca²⁺-ERK pathway is also involved in autophagy induction, which may be associated with the phosphorylation of Bcl-2, thereby resulting in Beclin 1 release from Bcl-2. In addition, Ca²⁺ can activate DAPK, which phosphorylates Beclin 1, thereby mediating its dissociation from Bcl-2. Vps34 may also be activated by Ca²⁺, although this activation is still debated. Lysosomal Ca²⁺ signaling could also induce autophagy. TRPML3, a Ca²⁺-permeable channel mainly expressed in lysosomes, facilitates autophagosome maturation by providing Ca²⁺ in the fusion process through a specific interaction with Atg8. MCOLN1 and lysosomal Ca²⁺ channel could induce autophagy by activating the calcineurin and its substrate TFEB. Furthermore, the plasma membrane Ca²⁺ channel MCOLN3 also activates autophagy