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Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics
Mitochondria undergo dynamic fusion/fission, biogenesis and mitophagy in response to stimuli or stresses. Disruption of mitochondrial homeostasis could lead to cell senescence, although the underlying mechanism remains unclear. We show that deletion of mitochondrial phosphatase PGAM5 leads to accele...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242393/ https://www.ncbi.nlm.nih.gov/pubmed/32439975 http://dx.doi.org/10.1038/s41467-020-16312-7 |
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author | Yu, Bo Ma, Jing Li, Jing Wang, Dazhi Wang, Zhigao Wang, Shusheng |
author_facet | Yu, Bo Ma, Jing Li, Jing Wang, Dazhi Wang, Zhigao Wang, Shusheng |
author_sort | Yu, Bo |
collection | PubMed |
description | Mitochondria undergo dynamic fusion/fission, biogenesis and mitophagy in response to stimuli or stresses. Disruption of mitochondrial homeostasis could lead to cell senescence, although the underlying mechanism remains unclear. We show that deletion of mitochondrial phosphatase PGAM5 leads to accelerated retinal pigment epithelial (RPE) senescence in vitro and in vivo. Mechanistically, PGAM5 is required for mitochondrial fission through dephosphorylating DRP1. PGAM5 deletion leads to increased mitochondrial fusion and decreased mitochondrial turnover. As results, cellular ATP and reactive oxygen species (ROS) levels are elevated, mTOR and IRF/IFN-β signaling pathways are enhanced, leading to cellular senescence. Overexpression of Drp1 K38A or S637A mutant phenocopies or rescues mTOR activation and senescence in PGAM5(−/−) cells, respectively. Young but not aging Pgam5(−/−) mice are resistant to sodium iodate-induced RPE cell death. Our studies establish a link between defective mitochondrial fission, cellular senescence and age-dependent oxidative stress response, which have implications in age-related diseases. |
format | Online Article Text |
id | pubmed-7242393 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-72423932020-05-29 Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics Yu, Bo Ma, Jing Li, Jing Wang, Dazhi Wang, Zhigao Wang, Shusheng Nat Commun Article Mitochondria undergo dynamic fusion/fission, biogenesis and mitophagy in response to stimuli or stresses. Disruption of mitochondrial homeostasis could lead to cell senescence, although the underlying mechanism remains unclear. We show that deletion of mitochondrial phosphatase PGAM5 leads to accelerated retinal pigment epithelial (RPE) senescence in vitro and in vivo. Mechanistically, PGAM5 is required for mitochondrial fission through dephosphorylating DRP1. PGAM5 deletion leads to increased mitochondrial fusion and decreased mitochondrial turnover. As results, cellular ATP and reactive oxygen species (ROS) levels are elevated, mTOR and IRF/IFN-β signaling pathways are enhanced, leading to cellular senescence. Overexpression of Drp1 K38A or S637A mutant phenocopies or rescues mTOR activation and senescence in PGAM5(−/−) cells, respectively. Young but not aging Pgam5(−/−) mice are resistant to sodium iodate-induced RPE cell death. Our studies establish a link between defective mitochondrial fission, cellular senescence and age-dependent oxidative stress response, which have implications in age-related diseases. Nature Publishing Group UK 2020-05-21 /pmc/articles/PMC7242393/ /pubmed/32439975 http://dx.doi.org/10.1038/s41467-020-16312-7 Text en © The Author(s) 2020 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/. |
spellingShingle | Article Yu, Bo Ma, Jing Li, Jing Wang, Dazhi Wang, Zhigao Wang, Shusheng Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics |
title | Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics |
title_full | Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics |
title_fullStr | Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics |
title_full_unstemmed | Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics |
title_short | Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics |
title_sort | mitochondrial phosphatase pgam5 modulates cellular senescence by regulating mitochondrial dynamics |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242393/ https://www.ncbi.nlm.nih.gov/pubmed/32439975 http://dx.doi.org/10.1038/s41467-020-16312-7 |
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