Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal
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- 4 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Chemical Biology
- Vol. 17 (4), 465-476
- https://doi.org/10.1038/s41589-020-00734-x
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.Keywords
Funding Information
- Narodowe Centrum Nauki (Grant 2019/35/D/ST4/02203)
- March of Dimes | March of Dimes Prematurity Research Center Ohio Collaborative
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NS076511, NS061817)
- National Natural Science Foundation of China (81873209, 81622050, 81903821)
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (HL114453)
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (AI156924, AI156923, AI145406)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (CA243142)
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