Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis

  • Nat Chem Biol. 2017 Jan;13(1):81-90. doi: 10.1038/nchembio.2238.
Valerian E Kagan  1  2  3  4 ,  Gaowei Mao  1  5 ,  Feng Qu  1 ,  Jose Pedro Friedmann Angeli  6 ,  Sebastian Doll  6 ,  Claudette St Croix  7 ,  Haider Hussain Dar  1 ,  Bing Liu  8 ,  Vladimir A Tyurin  1 ,  Vladimir B Ritov  1 ,  Alexandr A Kapralov  1 ,  Andrew A Amoscato  1 ,  Jianfei Jiang  1 ,  Tamil Anthonymuthu  5 ,  Dariush Mohammadyani  1 ,  Qin Yang  5 ,  Bettina Proneth  6 ,  Judith Klein-Seetharaman  9 ,  Simon Watkins  7 ,  Ivet Bahar  8 ,  Joel Greenberger  4 ,  Rama K Mallampalli  10 ,  Brent R Stockwell  11  12 ,  Yulia Y Tyurina  1 ,  Marcus Conrad  6 ,  Hülya Bayır  1  5
Affiliations
  • 1. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 2. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 3. Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 4. Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 5. Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 6. Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
  • 7. Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 8. Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 9. Division of Metabolic and Vascular Health, University of Warwick, Coventry, UK.
  • 10. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 11. Department of Biological Sciences, Columbia University, New York, New York, USA.
  • 12. Department of Chemistry, Columbia University, New York, New York, USA.
PMID: 27842066 DOI: 10.1038/nchembio.2238
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.