Cargando…

Lysosomal Ca(2+)-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress

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 metaboli...

Descripción completa

Detalles Bibliográficos
Autores principales: Park, Kihyoun, Lim, Hyejin, Kim, Jinyoung, Hwang, Yeseong, Lee, Yu Seol, Bae, Soo Han, Kim, Hyeongseok, Kim, Hail, Kang, Shin-Wook, Kim, Joo Young, Lee, Myung-Shik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921223/
https://www.ncbi.nlm.nih.gov/pubmed/35288580
http://dx.doi.org/10.1038/s41467-022-28874-9
_version_ 1784669290195058688
author Park, Kihyoun
Lim, Hyejin
Kim, Jinyoung
Hwang, Yeseong
Lee, Yu Seol
Bae, Soo Han
Kim, Hyeongseok
Kim, Hail
Kang, Shin-Wook
Kim, Joo Young
Lee, Myung-Shik
author_facet Park, Kihyoun
Lim, Hyejin
Kim, Jinyoung
Hwang, Yeseong
Lee, Yu Seol
Bae, Soo Han
Kim, Hyeongseok
Kim, Hail
Kang, Shin-Wook
Kim, Joo Young
Lee, Myung-Shik
author_sort Park, Kihyoun
collection PubMed
description 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 activity 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.
format Online
Article
Text
id pubmed-8921223
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-89212232022-04-01 Lysosomal Ca(2+)-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress Park, Kihyoun Lim, Hyejin Kim, Jinyoung Hwang, Yeseong Lee, Yu Seol Bae, Soo Han Kim, Hyeongseok Kim, Hail Kang, Shin-Wook Kim, Joo Young Lee, Myung-Shik Nat Commun Article 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 activity 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. Nature Publishing Group UK 2022-03-14 /pmc/articles/PMC8921223/ /pubmed/35288580 http://dx.doi.org/10.1038/s41467-022-28874-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Park, Kihyoun
Lim, Hyejin
Kim, Jinyoung
Hwang, Yeseong
Lee, Yu Seol
Bae, Soo Han
Kim, Hyeongseok
Kim, Hail
Kang, Shin-Wook
Kim, Joo Young
Lee, Myung-Shik
Lysosomal Ca(2+)-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress
title Lysosomal Ca(2+)-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress
title_full Lysosomal Ca(2+)-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress
title_fullStr Lysosomal Ca(2+)-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress
title_full_unstemmed Lysosomal Ca(2+)-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress
title_short Lysosomal Ca(2+)-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress
title_sort lysosomal ca(2+)-mediated tfeb activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921223/
https://www.ncbi.nlm.nih.gov/pubmed/35288580
http://dx.doi.org/10.1038/s41467-022-28874-9
work_keys_str_mv AT parkkihyoun lysosomalca2mediatedtfebactivationmodulatesmitophagyandfunctionaladaptationofpancreaticbcellstometabolicstress
AT limhyejin lysosomalca2mediatedtfebactivationmodulatesmitophagyandfunctionaladaptationofpancreaticbcellstometabolicstress
AT kimjinyoung lysosomalca2mediatedtfebactivationmodulatesmitophagyandfunctionaladaptationofpancreaticbcellstometabolicstress
AT hwangyeseong lysosomalca2mediatedtfebactivationmodulatesmitophagyandfunctionaladaptationofpancreaticbcellstometabolicstress
AT leeyuseol lysosomalca2mediatedtfebactivationmodulatesmitophagyandfunctionaladaptationofpancreaticbcellstometabolicstress
AT baesoohan lysosomalca2mediatedtfebactivationmodulatesmitophagyandfunctionaladaptationofpancreaticbcellstometabolicstress
AT kimhyeongseok lysosomalca2mediatedtfebactivationmodulatesmitophagyandfunctionaladaptationofpancreaticbcellstometabolicstress
AT kimhail lysosomalca2mediatedtfebactivationmodulatesmitophagyandfunctionaladaptationofpancreaticbcellstometabolicstress
AT kangshinwook lysosomalca2mediatedtfebactivationmodulatesmitophagyandfunctionaladaptationofpancreaticbcellstometabolicstress
AT kimjooyoung lysosomalca2mediatedtfebactivationmodulatesmitophagyandfunctionaladaptationofpancreaticbcellstometabolicstress
AT leemyungshik lysosomalca2mediatedtfebactivationmodulatesmitophagyandfunctionaladaptationofpancreaticbcellstometabolicstress