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

Kihyoun Park, Hyejin Lim, Jinyoung Kim, Yeseong Hwang, Yu Seol Lee, Soo Han Bae, Hyeongseok Kim, Hail Kim, Shin-Wook Kang, Joo Young Kim and Myung-Shik Lee ()
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Kihyoun Park: Yonsei University College of Medicine
Hyejin Lim: Yonsei University College of Medicine
Jinyoung Kim: Yonsei University College of Medicine
Yeseong Hwang: Yonsei University College of Medicine
Yu Seol Lee: Yonsei University College of Medicine
Soo Han Bae: Yonsei University College of Medicine
Hyeongseok Kim: Chungnam National University
Hail Kim: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology
Shin-Wook Kang: Yonsei University College of Medicine
Joo Young Kim: Department of Pharmacology and Brain Korea 21 Project for Medical Sciences
Myung-Shik Lee: Yonsei University College of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-17

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 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 (TfebΔβ-cell) abrogated high-fat diet (HFD)-induced mitophagy, accompanied by increased ROS and reduced mitochondrial cytochrome c oxidase activity or O2 consumption. TfebΔβ-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.

Date: 2022
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DOI: 10.1038/s41467-022-28874-9

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