Lysosomal Ca 2+ -mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress.

Although autophagy is critical for pancreatic β-cell function, the role and mechanism of mitophagy in β-cells are unclear. We studied the role of lysosomal Ca 2+ in TFEB activation by mitochondrial or metabolic stress and that of TFEB-mediated mitophagy in β-cell function. Mitochondrial or metabolic stress induced mitophagy through lysosomal Ca 2+ release, increased cytosolic Ca 2+ and TFEB activation. Lysosomal Ca 2+ replenishment by ER- > lysosome Ca 2+ refilling was essential for mitophagy. β-cell-specific Tfeb knockout (Tfeb Δβ-cell ) abrogated high-fat diet (HFD)-induced mitophagy, accompanied by increased ROS and reduced mitochondrial cytochrome c oxidase activity or O 2 consumption. Tfeb Δβ-cell mice showed aggravation of HFD-induced glucose intolerance and impaired insulin release. Metabolic or mitochondrial stress induced TFEB-dependent expression of mitophagy receptors including Ndp52 and Optn, contributing to the increased mitophagy. These results suggest crucial roles of lysosomal Ca 2+ release coupled with ER- > lysosome Ca 2+ refilling and TFEB activation in mitophagy and maintenance of pancreatic β-cell function during metabolic stress.