TY - JOUR
T1 - Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis
AU - Kagan, Valerian E.
AU - Mao, Gaowei
AU - Qu, Feng
AU - Angeli, Jose Pedro Friedmann
AU - Doll, Sebastian
AU - Croix, Claudette St
AU - Dar, Haider Hussain
AU - Liu, Bing
AU - Tyurin, Vladimir A.
AU - Ritov, Vladimir B.
AU - Kapralov, Alexandr A.
AU - Amoscato, Andrew A.
AU - Jiang, Jianfei
AU - Anthonymuthu, Tamil
AU - Mohammadyani, Dariush
AU - Yang, Qin
AU - Proneth, Bettina
AU - Klein-Seetharaman, Judith
AU - Watkins, Simon
AU - Bahar, Ivet
AU - Greenberger, Joel
AU - Mallampalli, Rama K.
AU - Stockwell, Brent R.
AU - Tyurina, Yulia Y.
AU - Conrad, Marcus
AU - Baylr, Hülya
N1 - Publisher Copyright:
© 2016 Nature America, Inc.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84995452435
U2 - 10.1038/nchembio.2238
DO - 10.1038/nchembio.2238
M3 - Article
C2 - 27842066
AN - SCOPUS:84995452435
SN - 1552-4450
VL - 13
SP - 81
EP - 90
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 1
ER -