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Tocopherols and tocotrienols prevent lipoxygenase‐driven phospholipid oxidation in ferroptosis
Author(s) -
Mao Gaowei,
Qu Feng,
Angeli Jose Pedro,
St Croix Claudette,
Dar Haider,
Tyurin Vladimir,
Ritov Vladimir,
Kapralov Alexandr,
Amoscato Andrew,
Anthonymuthu Tamil,
Mohammadyani Dariush,
Yang Qin,
Stockwell Brent,
Tyurina Yulia,
Conrad Marcus,
Bayır Hülya,
Kagan Valerian
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.946.3
Subject(s) - gpx4 , phospholipid hydroperoxide glutathione peroxidase , chemistry , endoplasmic reticulum , lipid peroxidation , biochemistry , phospholipid , lipoxygenase , vitamin e , peroxidase , microbiology and biotechnology , antioxidant , enzyme , glutathione peroxidase , glutathione , biology , membrane
Ferroptosis, a recently discovered regulated necrotic pathway, has been claimed to include a required stage of lipid peroxidation. However, neither the nature of oxidized lipid species nor their subcellular location and enzymatic generators have been identified. We established that inactivation or depletion of glutathione peroxidase 4 (Gpx4) induced ferroptosis in mouse embryonic fibroblasts (MEFs). Using mitochondria and endoplasmic reticulum (ER) targeted fluorogen‐activating proteins (Mito‐FAP and ER‐FAP), we demonstrated that generation of oxidized lipids predominantly occurred in the ER compartment. We further showed that oxidized arachidonoyl‐ and adrenoyl‐phosphatidylethanol‐amines (but not oxygenated free fatty acids) were the major players in the execution of ferroptosis. Formation of the oxidized phospholipids was predominantly catalyzed by 15‐lipoxygenases (LOX). Vitamin E homologues (tocopherols and tocotrienols) bind with the catalytic site of LOX and suppress ferroptosis, revealing a potential non‐canonical mechanism of action of vitamin E in protection against ferroptosis likely realized independently of radical scavenging. Taken together, these findings decipher molecular mechanisms of ferroptosis and provide new therapeutic targets. Support or Funding Information US National Institutes of Health (NS076511 to V.E.K., NS061817 to H.B., and ES020693 to Y.Y.T.), the Human Frontier Science Program (HFSP‐RGP0013/2014), and the Deutsche Forschungsgemeinschaft (CO 291/2‐3 and CO 291/5‐1) to M.C.