Cargando…
Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis
Necroptosis as a molecular program, rather than simply incidental cell death, was established by elucidating the roles of receptor interacting protein (RIP) kinases 1 and 3, along with their downstream partner, mixed lineage kinase-like domain protein (MLKL). Previous studies suggested that phosphog...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725845/ https://www.ncbi.nlm.nih.gov/pubmed/26807733 http://dx.doi.org/10.1371/journal.pone.0147792 |
_version_ | 1782411690656137216 |
---|---|
author | Lu, Wei Sun, Junhui Yoon, Jeong Seon Zhang, Yan Zheng, Lixin Murphy, Elizabeth Mattson, Mark P. Lenardo, Michael J. |
author_facet | Lu, Wei Sun, Junhui Yoon, Jeong Seon Zhang, Yan Zheng, Lixin Murphy, Elizabeth Mattson, Mark P. Lenardo, Michael J. |
author_sort | Lu, Wei |
collection | PubMed |
description | Necroptosis as a molecular program, rather than simply incidental cell death, was established by elucidating the roles of receptor interacting protein (RIP) kinases 1 and 3, along with their downstream partner, mixed lineage kinase-like domain protein (MLKL). Previous studies suggested that phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein that associates with RIP1/RIP3/MLKL complex, promotes necroptosis. We have generated mice deficient in the pgam5 gene and surprisingly found PGAM5-deficiency exacerbated rather than reduced necroptosis in response to multiple in vitro and in vivo necroptotic stimuli, including ischemic reperfusion injury (I/R) in the heart and brain. Electron microscopy, biochemical, and confocal analysis revealed that PGAM5 is indispensable for the process of PINK1 dependent mitophagy which antagonizes necroptosis. The loss of PGAM5/PINK1 mediated mitophagy causes the accumulation of abnormal mitochondria, leading to the overproduction of reactive oxygen species (ROS) that worsen necroptosis. Our results revise the former proposal that PGAM5 acts downstream of RIP1/RIP3 to mediate necroptosis. Instead, PGAM5 protects cells from necroptosis by independently promoting mitophagy. PGAM5 promotion of mitophagy may represent a therapeutic target for stroke, myocardial infarction and other diseases caused by oxidative damage and necroptosis. |
format | Online Article Text |
id | pubmed-4725845 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-47258452016-02-03 Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis Lu, Wei Sun, Junhui Yoon, Jeong Seon Zhang, Yan Zheng, Lixin Murphy, Elizabeth Mattson, Mark P. Lenardo, Michael J. PLoS One Research Article Necroptosis as a molecular program, rather than simply incidental cell death, was established by elucidating the roles of receptor interacting protein (RIP) kinases 1 and 3, along with their downstream partner, mixed lineage kinase-like domain protein (MLKL). Previous studies suggested that phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein that associates with RIP1/RIP3/MLKL complex, promotes necroptosis. We have generated mice deficient in the pgam5 gene and surprisingly found PGAM5-deficiency exacerbated rather than reduced necroptosis in response to multiple in vitro and in vivo necroptotic stimuli, including ischemic reperfusion injury (I/R) in the heart and brain. Electron microscopy, biochemical, and confocal analysis revealed that PGAM5 is indispensable for the process of PINK1 dependent mitophagy which antagonizes necroptosis. The loss of PGAM5/PINK1 mediated mitophagy causes the accumulation of abnormal mitochondria, leading to the overproduction of reactive oxygen species (ROS) that worsen necroptosis. Our results revise the former proposal that PGAM5 acts downstream of RIP1/RIP3 to mediate necroptosis. Instead, PGAM5 protects cells from necroptosis by independently promoting mitophagy. PGAM5 promotion of mitophagy may represent a therapeutic target for stroke, myocardial infarction and other diseases caused by oxidative damage and necroptosis. Public Library of Science 2016-01-25 /pmc/articles/PMC4725845/ /pubmed/26807733 http://dx.doi.org/10.1371/journal.pone.0147792 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication. |
spellingShingle | Research Article Lu, Wei Sun, Junhui Yoon, Jeong Seon Zhang, Yan Zheng, Lixin Murphy, Elizabeth Mattson, Mark P. Lenardo, Michael J. Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis |
title | Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis |
title_full | Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis |
title_fullStr | Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis |
title_full_unstemmed | Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis |
title_short | Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis |
title_sort | mitochondrial protein pgam5 regulates mitophagic protection against cell necroptosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725845/ https://www.ncbi.nlm.nih.gov/pubmed/26807733 http://dx.doi.org/10.1371/journal.pone.0147792 |
work_keys_str_mv | AT luwei mitochondrialproteinpgam5regulatesmitophagicprotectionagainstcellnecroptosis AT sunjunhui mitochondrialproteinpgam5regulatesmitophagicprotectionagainstcellnecroptosis AT yoonjeongseon mitochondrialproteinpgam5regulatesmitophagicprotectionagainstcellnecroptosis AT zhangyan mitochondrialproteinpgam5regulatesmitophagicprotectionagainstcellnecroptosis AT zhenglixin mitochondrialproteinpgam5regulatesmitophagicprotectionagainstcellnecroptosis AT murphyelizabeth mitochondrialproteinpgam5regulatesmitophagicprotectionagainstcellnecroptosis AT mattsonmarkp mitochondrialproteinpgam5regulatesmitophagicprotectionagainstcellnecroptosis AT lenardomichaelj mitochondrialproteinpgam5regulatesmitophagicprotectionagainstcellnecroptosis |