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Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis

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Kagan, Valerian E., Mao, Gaowei, Qu, Feng, Angeli, Jose Pedro Friedmann, Doll, Sebastian, Croix, Claudette St, Dar, Haider Hussain, Liu, Bing, Tyurin, Vladimir A., Ritov, Vladimir B. et al.
(2016) Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nature Chemical Biology, 13 (1). pp. 81-90. doi:10.1038/nchembio.2238

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Official URL: http://dx.doi.org/10.1038/nchembio.2238

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Abstract

Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis—a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls—arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.

Item Type: Journal Article
Divisions: Faculty of Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016)
Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine
Faculty of Medicine > Warwick Medical School
Journal or Publication Title: Nature Chemical Biology
Publisher: Nature Publishing Group
ISSN: 1552-4450
Official Date: 14 November 2016
Dates:
DateEvent
14 November 2016Published
3 October 2016Accepted
3 March 2016Submitted
Volume: 13
Number: 1
Page Range: pp. 81-90
DOI: 10.1038/nchembio.2238
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access

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