Oxidized Arachidonic/Adrenic Phosphatidylethanolamines Navigate Cells to Ferroptosis

By V. Kagan, G. Mao, F. Qu, J. Angeli, S. Doll, C. Croix, H. Dar, B. Liu, V. Tyurin, V. Ritov and 16 more. Nature Chemical Biology, 2016

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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). Here, by using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology we discovered that execution of ferroptosis involves a highly organized oxygenation center, whereby only one class of phospholipids, phosphatidylethanolamines (PE), undergoes oxidation in the ER-associated compartments with the specificity towards 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 acts as a specific anti-ferroptotic rescue pathway. Lipoxygenases (LOX) generate doubly- and triply-oxygenated (15-hydroperoxy)-di-acylated PE species which act as death signals while tocopherols and tocotrienols suppress LOX and protect against ferroptosis suggesting an unforeseen homeostatic physiological role of vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.

Subfields: Immunology, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/2c2328c19587362d575b52d607d4c6ad74b1fd70

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Citations in the corpus

Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State (2019, neutral): “The role of ACSL4 in the protective effects of exogenous MUFAs could not be determined, as deletion of this protein made cells insensitive to erastin2, consistent with recent reports (Dixon et al., 2015; Doll et al., 2017; Kagan et al., 2017) (Figure 5A).”
Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity (2020, neutral): “peroxidation by the Fenton reaction with cytosolic Fe2+ in RSL3- or erastin-induced ferroptosis (39).”
PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals (2017, methodology): “(legend continued on next page) Cell 171, 628–641, October 19, 2017 629 as a pivot point between cell survival and ferroptosis (Kagan et al., 2017).”
CD8+ T cells regulate tumor ferroptosis during cancer immunotherapy (2019, methodology): “Moreover, using liquid chromatography-mass spectrometry (LC-MS) 7,8 , we detected the increases of oxidized phosphatidylethanolamine (PE) (Extended Data Fig.”
Ferroptosis as a target for protection against cardiomyopathy (2019, background): “Previous studies showed that phosphatidylethanolamines (PEs) are key phospholipids (PLs) that undergo oxidation, driving ferroptosis (32, 33).”
Autophagy-Dependent Ferroptosis: Machinery and Regulation (2020, background): “The activation of the GPX4, AIFM2, or ESCRT-III pathways can limit or repair the oxidation of PUFAs that result from the activation of the ACSL4-LPCAT3-ALOX pathway.”
Ferroptosis: mechanisms and links with diseases (2021, methodology): “It has been reported that this reaction may occur on the mitochondrial membrane(1) or the mitochondrial and endoplasmic reticulum membrane.(11) BID (a pro-apoptotic protein) links mitochondria with ferroptosis,(47) and the mitochondrial TCA cycle promotes ferroptosis.”
FINO2 Initiates Ferroptosis Through GPX4 Inactivation and Iron Oxidation (2018, neutral): “These epoxides were then heated under basic conditions to afford oxetanes 14 - 16 .”
The Development of the Concept of Ferroptosis (2018, neutral): “2017 Phosphatidylethanolamines (PEs) are the fatty acids oxidized in the ER through ferroptosis [26]”
Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “In the presence of long-chain fatty acid–CoA ligase 4 (ACSL4) and lysophospholipid acyltransferase 5 (LPCAT3), polyunsaturated fatty acid (PUFA) is catalyzed to develop phospholipids-polyunsaturated fatty acid (PL-PUFA).(82,83) Finally, PL-PUFA is mediated by ALOXs Autophagy, ferroptosis, pyroptosis”
The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity. (2017, neutral): “In particular, acetyl coenzyme A (acyl-CoA) synthetase long-chain family member 4 (ACSL4) is critical for lipid peroxidation in ferroptotic cell death due to catalyzing esterification of arachidonoyl or adrenoyl into phosphatidylethanolamines (Doll et al., 2017; Kagan et al., 2017; Yuan et al., 2016”
Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones (2023, background): “Previous studies suggest that PEs with arachidonoyl tail (PE-AA, 20:4) or adrenoyl tail (PE-AdA, 22:4) are the major PL-PUFAs that are subjected to peroxidation during ferroptosis.(24,25) Since MBOAT2 mainly affects PE lipids, we propose that MBOAT2 selectively transfers MUFA-CoA to lysoPE to compet”