Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal

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. AmoscatoTeresa G. Hastings, Timothy J. Greenamyre, Charleen T. Chu, Yoel Sadovsky, Ivet Bahar, Hülya Bayır, Yulia Y. Tyurina, Rong Rong He, Valerian E. Kagan

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)465-476
Number of pages12
JournalNature Chemical Biology
Volume17
Issue number4
DOIs
StatePublished - 1 Apr 2021
Externally publishedYes

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