Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal.

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 Ca2+-independent phospholipase A2β (iPLA2β, 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, iPLA2β 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 (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9R748W/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 SncaA53T mice, with decreased iPLA2β expression and a PD-relevant phenotype. Thus, iPLA2β is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.

Citation

Wan-Yang Sun, Vladimir A Tyurin, Karolina Mikulska-Ruminska, Indira H Shrivastava, Tamil S Anthonymuthu, Yu-Jia Zhai, Ming-Hai Pan, Hai-Biao Gong, Dan-Hua Lu, Jie Sun, Wen-Jun Duan, Sergey Korolev, Andrey Y Abramov, Plamena R Angelova, Ian Miller, Ofer Beharier, Gao-Wei Mao, Haider H Dar, Alexandr A Kapralov, Andrew A Amoscato, Teresa G Hastings, Timothy J Greenamyre, Charleen T Chu, Yoel Sadovsky, Ivet Bahar, Hülya Bayır, Yulia Y Tyurina, Rong-Rong He, Valerian E Kagan. Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal. Nature chemical biology. 2021 Apr;17(4):465-476

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PMID: 33542532

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