Journal
NATURE CHEMICAL BIOLOGY
Volume 13, Issue 1, Pages 81-90Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2238
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Funding
- US National Institutes of Health [P01HL114453, U19AI068021, N5076511, N5061817, P41GM103712, ES020693]
- Human Frontier Science Program [HFSP-RGP0013/2014]
- Deutsche Forschungsgemeinschaft [CO 291/2-3, CO 291/5-1]
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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.
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