title: Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis.
abstract: 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.
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: Systems Biology Center,National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Junhui
authors.initials: J
authors.lastname: Sun
authors.affiliation: Cellular and Molecular Neuroscience Section, Laboratory of Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Jeong Seon
authors.initials: JS
authors.lastname: Yoon
authors.affiliation: Molecular Mechanism of Apoptosis Section, Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Lixin
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Systems Biology Center,National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Murphy
authors.affiliation: Cellular and Molecular Neuroscience Section, Laboratory of Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D063306:Mitophagy / Q000502:physiology*; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism; D009336:Necrosis / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; C570696:PGAM5 protein, mouse; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases