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Lysosomal Ca 2+-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  ;  Myung-Shik Lee 
 NATURE COMMUNICATIONS, Vol.13(1) : 1300, 2022-03 
Journal Title
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Animals ; Autophagy / physiology ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism ; Lysosomes* / metabolism ; Mice ; Mitochondria / metabolism ; Mitophagy* / physiology ; Stress, Physiological
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kang, Shin Wook(강신욱) ORCID logo https://orcid.org/0000-0002-5677-4756
Kim, Joo Young(김주영) ORCID logo https://orcid.org/0000-0003-2623-1491
Kim, Jinyoung(김진영) ORCID logo https://orcid.org/0000-0002-3810-8549
Bae, Soo Han(배수한) ORCID logo https://orcid.org/0000-0002-8007-2906
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
Lim, Hyejin(임혜진)
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