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Cited by 337Ferroptosis and cancer prognosisNeurological diseases and metabolismParkinson's Disease Mechanisms and Treatments

Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal

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Sun, Wan-Yang, Tyurin, Vladimir A., Mikulska-Ruminska, Karolina, Shrivastava, Indira H., Anthonymuthu, Tamil S., Zhai, Yu-Jia, Pan, Ming-Hai, Gong, Hai-Biao +21 more·2021·Nature Chemical Biology
DOI 10.1038/s41589-020-00734-xPMC PMC8152680
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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 2+-independent phospholipase A 2 β (iPLA 2 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 2 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 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 a PD-relevant phenotype. Thus, iPLA 2 β is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.

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  • Each type of PLA2 has substrate-specific activity, and depending on the substrate, PLA2 can either promote or block ferroptosis.

    “Each type of PLA2 has a substrate-specific activity, and depending on the substrate, PLA2 can either promote or block ferroptosis (28–31).”

    From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [29]

    The Discussion (page not available in our copy) describes iPLA2β’s preference for arachidonoyl substrates and its anti-ferroptotic removal of peroxidized phospholipids. It speculates that activity toward triacylglycerols could indirectly enhance ferroptosis by diverting iPLA2β, but does not establish that each type of PLA2 has a distinct substrate specificity or that PLA2 types can directly promote or block ferroptosis depending on their substrate. (LLM, conf=0.84)

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References 56 · Cited by 337

Research works printed but not linked: 47

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Authors
Sun, W.-Y., Tyurin, V. A., Mikulska-Ruminska, K., Shrivastava, I. H., Anthonymuthu, T. S., Zhai, Y.-J., Pan, M.-H., Gong, H.-B., Lu, D.-H., Sun, J., Duan, W.-J., Korolev, S., Abramov, A. Y., Angelova, P. R., Miller, I., Beharier, O., Mao, G.-W., Dar, H. H., Kapralov, A. A., Amoscato, A. A., Hastings, T. G., Greenamyre, T. J., Chu, C. T., Sadovsky, Y., Bahar, I., Bayır, H., Tyurina, Y. Y., He, R.-R., & Kagan, V. E.
Affiliations
  • Jinan University (CN)
  • University of Pittsburgh (US)
  • Saint Louis University (US)
  • UCL Queen Square Institute of Neurology (GB)
Corresponding author
  • Tyurina, Yulia Y.
  • He, Rong-Rong
  • Kagan, Valerian E.
ORCID
Venue
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Published
2021-02-04
Volume
17
Issue
4
Pages
465-476
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
DOI
10.1038/s41589-020-00734-x
PMC
PMC8152680
OpenAlex
W3126951521
Cited by
337
References
56
Citations by year
2026: 51 · 2025: 59 · 2024: 72 · 2023: 76 · 2022: 52 · 2021: 27
FWCI
36.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • 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)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
ferroptosis, PLA2G6, 15-lipoxygenase, lipid peroxidation, Parkinson's disease, neurodegeneration, rotenone, alpha-synuclein, phosphatidylethanolamine hydrolysis
MeSH terms
Ferroptosis, Animals, Arachidonate 15-Lipoxygenase, Disease Models, Animal, Female, Humans, Iron, Lipid Peroxides, Lipids, Male, Mice, Inbred C57BL, Oxidation-Reduction, Parkinson Disease, Phospholipases, Phospholipids, Rats, Inbred Lew, Leukotrienes, Phosphatidylethanolamine Binding Protein, Lipid Metabolism, Mice, Rats, Group VI Phospholipases A2

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