Lysosomal Ca-mediated TFEB Activation Modulates Mitophagy and Functional Adaptation of Pancreatic β-cells to Metabolic Stress

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Mar 15

PMID 35288580

Authors

Kihyoun Park

Hyejin Lim

Jinyoung Kim

Yeseong Hwang

Yu Seol Lee

Soo Han Bae

Hyeongseok Kim

Hail Kim

Shin-Wook Kang

Joo Young Kim

Myung-Shik Lee

Affiliations

Soon will be listed here.

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 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 release, increased cytosolic Ca and TFEB activation. Lysosomal Ca replenishment by ER- > lysosome Ca refilling was essential for mitophagy. β-cell-specific Tfeb knockout (Tfeb) abrogated high-fat diet (HFD)-induced mitophagy, accompanied by increased ROS and reduced mitochondrial cytochrome c oxidase activity or O consumption. Tfeb 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 release coupled with ER- > lysosome Ca refilling and TFEB activation in mitophagy and maintenance of pancreatic β-cell function during metabolic stress.

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