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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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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 |
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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 |
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