Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis

Valerian Kagan, Gaowei Mao, Feng Qu, Jose Angeli, Sebastian Doll, Claudette Croix, Haider Dar, Bing Liu, Vladimir Tyurin, Vladimir Ritov, Alexandr Kapralov, Andrew Amoscato, Jianfei Jiang, Tamil Anthonymuthu, Dariush Mohammadyani, Qin Yang, Bettina Proneth, Judith Klein-Seetharaman, Simon Watkins, Ivet Bahar, Joel Greenberger, Rama Mallampalli, Brent Stockwell, Yulia Tyurina, Marcus Conrad, Hülya Bayır (2017) Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis Nat Chem Biol (IF: 13.7) 13(1) 81-90

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.

Links

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506843
http://www.ncbi.nlm.nih.gov/pubmed/27842066
http://dx.doi.org/10.1038/nchembio.2238

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