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      Oxidized Arachidonic/Adrenic Phosphatidylethanolamines Navigate Cells to Ferroptosis

      1 , 2 , 3 , 4 , 1 , 1 , 5 , 5 , 6 , 1 , 7 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 5 , 1 , 6 , 7 , 4 , 8 , 10 , 1 , 5 , 1 , 9
      Nature chemical biology
      ferroptosis, phosphatidylethanolamine peroxidation, acyl-CoA synthase 4, glutathione peroxidase 4, 15-lipoxygenase, tocopherols and tocotrienols

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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.

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          ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.

          Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.
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            Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death.

            Oxidative stress in conjunction with glutathione depletion has been linked with various acute and chronic degenerative disorders, yet the molecular mechanisms have remained unclear. In contrast to the belief that oxygen radicals are detrimental to cells and tissues by unspecific oxidation of essential biomolecules, we now demonstrate that oxidative stress is sensed and transduced by glutathione peroxidase 4 (GPx4) into a-yet-unrecognized cell-death pathway. Inducible GPx4 inactivation in mice and cells revealed 12/15-lipoxygenase-derived lipid peroxidation as specific downstream event, triggering apoptosis-inducing factor (AIF)-mediated cell death. Cell death could be entirely prevented either by alpha-tocopherol (alpha-Toc), 12/15-lipoxygenase inhibitors, or siRNA-mediated AIF silencing. Accordingly, 12/15-lipoxygenase-deficient cells were highly resistant to glutathione depletion. Neuron-specific GPx4 depletion caused neurodegeneration in vivo and ex vivo, highlighting the importance of this pathway in neuronal cells. Since oxidative stress is common in the etiology of many human disorders, the identified pathway reveals promising targets for future therapies.
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              Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death

              Little is known about the regulation of nonapoptotic cell death. Using massive insertional mutagenesis of haploid KBM7 cells we identified nine genes involved in small-molecule-induced nonapoptotic cell death, including mediators of fatty acid metabolism (ACSL4) and lipid remodeling (LPCAT3) in ferroptosis. One novel compound, CIL56, triggered cell death dependent upon the rate-limiting de novo lipid synthetic enzyme ACC1. These results provide insight into the genetic regulation of cell death and highlight the central role of lipid metabolism in nonapoptotic cell death.

                Author and article information

                Nat Chem Biol
                Nat. Chem. Biol.
                Nature chemical biology
                11 May 2017
                14 November 2016
                January 2017
                12 July 2017
                : 13
                : 1
                : 81-90
                [1 ]Department of Environmental and Occupational Health, University of Pittsburgh, Germany
                [2 ]Department of Pharmacology and Chemical Biology, University of Pittsburgh, Germany
                [3 ]Department of Chemistry, University of Pittsburgh, Germany
                [4 ]Department of Radiation Oncology, University of Pittsburgh, Germany
                [5 ]Department of Helmholtz Zentrum München, Institute of Developmental Genetics, Germany
                [6 ]Department of Cell Biology, University of Pittsburgh, New York
                [7 ]Department of Computational and Systems Biology, University of Pittsburgh, New York
                [8 ]Department of Medicine, University of Pittsburgh, New York
                [9 ]Department of Critical Care Medicine, University of Pittsburgh, New York
                [10 ]Department of Biological Sciences and Chemistry, Columbia University, New York
                Author notes
                [* ]Correspondence to: Valerian E. Kagan ( Kagan@ 123456pitt.edu ), Marcus Conrad ( marcus.conrad@ 123456helmholtz-muenchen.de ), Hülya Bayır ( bayihx@ 123456ccm.upmc.edu )

                equal contribution

                PMC5506843 PMC5506843 5506843 nihpa873824

                ferroptosis,phosphatidylethanolamine peroxidation,acyl-CoA synthase 4,glutathione peroxidase 4,15-lipoxygenase,tocopherols and tocotrienols


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