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      Regulation of lipid peroxidation and ferroptosis in diverse species

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          Abstract

          This review by Conrad et al. reviews the functions and regulation of lipid peroxidation, ferroptosis, and the antioxidant network in diverse species, including humans, other mammals and vertebrates, plants, invertebrates, yeast, bacteria, and archaea, and discusses the potential evolutionary roles of lipid peroxidation and ferroptosis.

          Abstract

          Lipid peroxidation is the process by which oxygen combines with lipids to generate lipid hydroperoxides via intermediate formation of peroxyl radicals. Vitamin E and coenzyme Q 10 react with peroxyl radicals to yield peroxides, and then these oxidized lipid species can be detoxified by glutathione and glutathione peroxidase 4 (GPX4) and other components of the cellular antioxidant defense network. Ferroptosis is a form of regulated nonapoptotic cell death involving overwhelming iron-dependent lipid peroxidation. Here, we review the functions and regulation of lipid peroxidation, ferroptosis, and the antioxidant network in diverse species, including humans, other mammals and vertebrates, plants, invertebrates, yeast, bacteria, and archaea. We also discuss the potential evolutionary roles of lipid peroxidation and ferroptosis.

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)
          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

            Suzy Torti, Donna D. Zhang, K.A. Woerpel … (2019)
            Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
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              Regulation of ferroptotic cancer cell death by GPX4.

              Wan Seok Yang, Rohitha SriRamaratnam, Matthew E Welsch … (2014)
              Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Genes Dev
                Journal ID (iso-abbrev): Genes Dev
                Journal ID (hwp): genesdev
                Journal ID (pmc): genesdev
                Journal ID (publisher-id): GAD
                Title: Genes & Development
                Publisher: Cold Spring Harbor Laboratory Press
                ISSN (Print): 0890-9369
                ISSN (Electronic): 1549-5477
                Publication date (Print): 1 May 2018
                Volume: 32
                Issue: 9-10
                Pages: 602-619
                Affiliations
                [1 ]Institute of Developmental Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), 85764 Neuherberg, Germany;
                [2 ]Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA;
                [3 ]Department of Environmental Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA;
                [4 ]Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA;
                [5 ]Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA;
                [6 ]Laboratory of Navigational Lipidomics of Cell Death and Regeneration, I.M. Sechenov First Moscow State Medical University, Moscow 119992, Russia;
                [7 ]Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA;
                [8 ]Instituto de Investigaciones Biológicas, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Mar del Plata, 7600 Mar del Plata, Argentina;
                [9 ]Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97330;
                [10 ]Molecular and Cell Biology Graduate Program, Oregon State University, Corvallis, Oregon 97330, USA;
                [11 ]College of Public Health and Human Sciences, Oregon State University, Corvallis, Oregon 97330, USA;
                [12 ]Department of Biological Sciences, Columbia University, New York, New York 10027, USA;
                [13 ]Department of Chemistry, Columbia University, New York, New York 10027, USA
                Author notes
                Corresponding author: bstockwell@ 123456columbia.edu
                Author information
                http://orcid.org/0000-0002-3532-3868
                Article
                Medline ID: 8711660
                DOI: 10.1101/gad.314674.118
                PMC ID: 6004068
                PubMed ID: 29802123
                SO-VID: 60fee12b-f948-446d-9ff3-ba835c43c2a6
                Copyright © © 2018 Conrad et al.; Published by Cold Spring Harbor Laboratory Press
                License:

                This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Page count
                Pages: 18
                Funding
                Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;
                Award ID: R35CA209896
                Award ID: P01CA087497
                Award ID: U19AI068021
                Award ID: NS076511
                Award ID: NS061817
                Funded by: Deutsche Forschungsgemeinschaft , open-funder-registry 10.13039/501100001659;
                Award ID: CO 291/2-3
                Award ID: CO 291/5-1
                Funded by: Human Frontier Science Program , open-funder-registry 10.13039/100004412;
                Award ID: RGP0013
                Funded by: Agencia Nacional de Promoción Científica y Tecnológica , open-funder-registry 10.13039/501100003074;
                Funded by: Proyectos de Investigación Científica y Tecnológica
                Award ID: 2013-1372
                Award ID: PICT 2016-0110
                Categories
                Subject: 4
                Subject: Review

                Keywords: ferroptosis,lipid peroxidation,cell death,iron,ros,vitamin e
                Data availability:
                Keywords: ferroptosis, lipid peroxidation, cell death, iron, ros, vitamin e

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