Phospholipase iPLA(2)β Averts Ferroptosis By Eliminating A Redox Lipid Death Signal

Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to accumulation of 15-hydroperoxy-arachidonoyl-PE (15-HpETE-PE) generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, PEBP1. As Ca(2+)-independent phospholipase PLA(2) (iPLA(2)β, PLA2G6/PNPLA9 gene), can preferentially hydrolyze peroxidized phospholipids, it may eliminate 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/PNPLA9 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 PD-relevant phenotype. Thus, iPLA(2)β is a new ferroptosis regulator and its mutations may be implicated in PD pathogenesis.