Open AccessPhospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal
Author(s) -
WanYang Sun,
Vladimir A. Tyurin,
Karolina MikulskaRuminska,
Indira H. Shrivastava,
Tamil S. Anthonymuthu,
Yujia Zhai,
MingHai Pan,
Haibiao Gong,
Dan-Hua Lu,
Jie Sun,
Wen-Jun Duan,
Sergey Korolev,
Andrey Y. Abramov,
Plamena R. Angelova,
Ian Miller,
Ofer Beharier,
Gaowei Mao,
Haider H. Dar,
Alexandr A. Kapralov,
Andrew A. Amoscato,
Teresa G. Hastings,
Timothy J Greenamyre,
Charleen T. Chu,
Yoel Sadovsky,
İvet Bahar,
Hülya Bayır,
Yulia Y. Tyurina,
RongRong He,
Valerian E. Kagan
Publication year - 2021
Publication title -
nature chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.412
H-Index - 216
eISSN - 1552-4469
pISSN - 1552-4450
DOI - 10.1038/s41589-020-00734-x
Subject(s) - phosphatidylethanolamine , neurodegeneration , chemistry , phospholipase , mutant , phospholipase d , microbiology and biotechnology , biochemistry , biology , phosphatidylcholine , signal transduction , enzyme , gene , phospholipid , medicine , disease , pathology , membrane
Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca 2+ -independent phospholipase A 2 β (iPLA 2 β, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA 2 β averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson's disease (PD)-associated mutation (fPD R747W ) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9 R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant Snca A53T mice, with decreased iPLA 2 β expression and a PD-relevant phenotype. Thus, iPLA 2 β is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.