Oxidized Arachidonic and Adrenic PEs Navigate Cells to Ferroptosis

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2016 Nov 15

PMID 27842066

Citations 1163

Authors

Valerian E Kagan

Gaowei Mao

Feng Qu

Jose Pedro Friedmann Angeli

Sebastian Doll

Claudette St Croix

Haider Hussain Dar

Bing Liu

Vladimir A Tyurin

Vladimir B Ritov

Alexandr A Kapralov

Andrew A Amoscato

Jianfei Jiang

Tamil Anthonymuthu

Dariush Mohammadyani

Qin Yang

Bettina Proneth

Judith Klein-Seetharaman

Simon Watkins

Ivet Bahar

Joel Greenberger

Rama K Mallampalli

Brent R Stockwell

Yulia Y Tyurina

Marcus Conrad

Hulya Bayir

Affiliations

Soon will be listed here.

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.

Citing Articles

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