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

ABSTRACT: 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 show

SUBMITTER: Park K 

PROVIDER: S-EPMC8921223 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature