Regulation of autophagy by perilysosomal calcium: a new player in β-cell lipotoxicity
Ha Thu Nguyen, Andreas Wiederkehr, Claes B. Wollheim, Kyu‐Sang Park
Abstract
Abstract Autophagy is an essential quality control mechanism for maintaining organellar functions in eukaryotic cells. Defective autophagy in pancreatic beta cells has been shown to be involved in the progression of diabetes through impaired insulin secretion under glucolipotoxic stress. The underlying mechanism reveals the pathologic role of the hyperactivation of mechanistic target of rapamycin (mTOR), which inhibits lysosomal biogenesis and autophagic processes. Moreover, accumulating evidence suggests that oxidative stress induces Ca 2+ depletion in the endoplasmic reticulum (ER) and cytosolic Ca 2+ overload, which may contribute to mTOR activation in perilysosomal microdomains, leading to autophagic defects and β-cell failure due to lipotoxicity. This review delineates the antagonistic regulation of autophagic flux by mTOR and AMP-dependent protein kinase (AMPK) at the lysosomal membrane, and both of these molecules could be activated by perilysosomal calcium signaling. However, aberrant and persistent Ca 2+ elevation upon lipotoxic stress increases mTOR activity and suppresses autophagy. Therefore, normalization of autophagy is an attractive therapeutic strategy for patients with β-cell failure and diabetes.