Figure 1.

Proposed coordination of pathways that regulate the autophagy-lysosome System (ALS). ROS and cytosolic calcium ([Ca²⁺]_IC) act as upstream signaling mechanisms that converge on the gene expression and protein activation of the ALS. AMPK is activated directly via compromised energy status (increase AMP:ADP), and indirectly through [Ca²⁺]_IC via CaMKII (not shown). Elevated [Ca²⁺]_IC may occur due to the damaging effects of elevated ROS, from mitochondria or other sources, on the sarcoplasmic reticulum and lysosomes. AMPK synchronously activates FoxO3, Tfeb and Tfe3 (Tfeb/3) through (1) direct phosphorylation of FoxO3, (2) activation of TSC1/2 and (3) inhibition of mTORC1. Simultaneously, AMPK activates autophagy induction through the Ulk1 complex and by alleviating mTORC1 inhibition on this complex. In a similar cellular milieu, FoxO3 repression is alleviated via AKT inhibition. Increases in [Ca²⁺]_IC activate the phosphatase CnA, which activates Tfeb/3. ROS also activate Tfeb/3 through oxidation, an added layer of coordination in this autophagy-lysosome system.