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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 -  &gt; 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 a c tivity 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 -  &gt; lysosome Ca 2+  refilling and TFEB activation in mitophagy and maintenance of pancreatic β-cell function during metabolic stress.

Lysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress