Lysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress
Kihyoun Park, H.J. Lim, Jinyoung Kim, Yeseong Hwang, Yu Seol Lee, Soo Han Bae, Hyeongseok Kim, Hail Kim, Shin‐Wook Kang, Joo Young Kim, Myung‐Shik Lee
Abstract
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 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 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 - > lysosome Ca 2+ refilling and TFEB activation in mitophagy and maintenance of pancreatic β-cell function during metabolic stress.