Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis

被引：124

作者：

Lu, Wei ^{[1
]}

Sun, Junhui ^{[2
]}

Yoon, Jeong Seon ^{[3
]}

Zhang, Yan ^{[4
]}

Zheng, Lixin ^{[1
]}

Murphy, Elizabeth ^{[2
]}

Mattson, Mark P. ^{[3
]}

Lenardo, Michael J. ^{[1
]}

机构：

[1] NIAID, Mol Dev Immune Syst Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[2] NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA

[3] NIA, Cellular & Mol Neurosci Sect, Lab Neurosci, NIH, Baltimore, MD 21224 USA

[4] NCI, Mol Mech Apoptosis Sect, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA

来源：

PLOS ONE | 2016年 / 11卷 / 01期

基金：

美国国家卫生研究院;

关键词：

RECEPTOR-INTERACTING PROTEIN; MIXED LINEAGE KINASE; PROGRAMMED NECROSIS; DEATH; PHOSPHATASE; RIP3; PHOSPHORYLATION; APOPTOSIS; TRIGGERS; DYNAMICS;

D O I：

10.1371/journal.pone.0147792

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

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