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Nat Chem Biol. 2017 Jan;13(1):81-90. doi: 10.1038/nchembio.2238. Epub 2016 Nov 14.

Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis.

Author information

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.

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.

PMID:
27842066
PMCID:
PMC5506843
DOI:
10.1038/nchembio.2238
[Indexed for MEDLINE]
Free PMC Article

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