mTOR-Controlled Autophagy Requires Intracellular Ca2+ Signaling

Autophagy is a lysosomal degradation pathway important for cellular homeostasis and survival. Inhibition of the mammalian target of rapamycin (mTOR) is the best known trigger for autophagy stimulation. In addition, intracellular Ca2+ regulates autophagy, but its exact role remains ambiguous. Here, we report that the mTOR inhibitor rapamycin, while enhancing autophagy, also remodeled the intracellular Ca2+-signaling machinery. These alterations include a) an increase in the endoplasmic-reticulum (ER) Ca2+-store content, b) a decrease in the ER Ca2+-leak rate, and c) an increased Ca2+ release through the inositol 1,4,5-trisphosphate receptors (IP3Rs), the main ER-resident Ca2+-release channels. Importantly, buffering cytosolic Ca2+ with BAPTA impeded rapamycin-induced autophagy. These results reveal intracellular Ca2+ signaling as a crucial component in the canonical mTOR-dependent autophagy pathway.