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Phospholipase iPLA 2 β averts ferroptosis by eliminating a redox lipid death signal.
- Source :
-
Nature chemical biology [Nat Chem Biol] 2021 Apr; Vol. 17 (4), pp. 465-476. Date of Electronic Publication: 2021 Feb 04. - Publication Year :
- 2021
-
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 Ca <superscript>2+</superscript> -independent phospholipase A <subscript>2</subscript> β (iPLA <subscript>2</subscript> β, 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, iPLA <subscript>2</subscript> β 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 (fPD <superscript>R747W</superscript> ) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9 <superscript>R748W/R748W</superscript> 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 <superscript>A53T</superscript> mice, with decreased iPLA <subscript>2</subscript> β expression and a PD-relevant phenotype. Thus, iPLA <subscript>2</subscript> β is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.
- Subjects :
- Animals
Arachidonate 15-Lipoxygenase metabolism
Disease Models, Animal
Female
Group VI Phospholipases A2 physiology
Humans
Iron metabolism
Leukotrienes metabolism
Lipid Metabolism physiology
Lipid Peroxides metabolism
Lipids physiology
Male
Mice
Mice, Inbred C57BL
Oxidation-Reduction
Parkinson Disease metabolism
Phosphatidylethanolamine Binding Protein metabolism
Phospholipases metabolism
Phospholipids metabolism
Rats
Rats, Inbred Lew
Ferroptosis physiology
Group VI Phospholipases A2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4469
- Volume :
- 17
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Nature chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 33542532
- Full Text :
- https://doi.org/10.1038/s41589-020-00734-x