Details

Autor(en) / Beteiligte

• 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
• Kapralov, Alexandr A
• Amoscato, Andrew A
• Jiang, Jianfei
• Anthonymuthu, Tamil
• Mohammadyani, Dariush
• Yang, Qin
• Proneth, Bettina
• Klein-Seetharaman, Judith
• Watkins, Simon
• Bahar, Ivet
• Greenberger, Joel
• Mallampalli, Rama K
• Stockwell, Brent R
• Tyurina, Yulia Y
• Conrad, Marcus
• Bayır, Hülya

Titel

Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis

Ist Teil von

• Nature chemical biology, 2017-01, Vol.13 (1), p.81-90

Ort / Verlag

United States

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.