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Publication Detail
Phospholipase iPLA₂β averts ferroptosis by eliminating a redox lipid death signal
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Sun W-Y, Tyurin VA, Mikulska-Ruminska K, Shrivastava IH, Anthonymuthu TS, Zhai Y-J, Pan M-H, Gong H-B, Lu D-H, Sun J, Duan W-J, Korolev S, Abramov AY, Angelova PR, Miller I, Beharier O, Mao G-W, Dar HH, Kapralov AA, Amoscato AA, Hastings TG, Greenamyre TJ, Chu CT, Sadovsky Y, Bahar I, Bayır H, Tyurina YY, He R-R, Kagan VE
  • Publication date:
    01/04/2021
  • Journal:
    Nature Chemical Biology
  • Status:
    Published
  • Country:
    United States
  • PII:
    10.1038/s41589-020-00734-x
  • Language:
    eng
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.
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