Lysosomal Ca²⁺-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 Ca²⁺ 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 Ca²⁺ release, increased cytosolic Ca²⁺ and TFEB activation. Lysosomal Ca²⁺ replenishment by ER- > lysosome Ca²⁺ 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 O₂ 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 Ca²⁺ release coupled with ER- > lysosome Ca²⁺ refilling and TFEB activation in mitophagy and maintenance of pancreatic β-cell function during metabolic stress.