Tags

Type your tag names separated by a space and hit enter

FSP1 is a glutathione-independent ferroptosis suppressor.
Nature 2019Nat

Abstract

Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids1,2. To date, ferroptosis has been believed to be restrained only by the phospholipid hydroperoxide (PLOOH)-reducing enzyme glutathione peroxidase 4 (GPX4)3,4 and radical-trapping antioxidants (RTAs)5,6. The factors which underlie a given cell type's sensitivity to ferroptosis7 are, however, critical to understand the pathophysiological role of ferroptosis and how it may be exploited for cancer treatment. Although metabolic constraints8 and phospholipid composition9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been yet been identified that account for ferroptosis resistance. We undertook an expression cloning approach to identify genes able to complement GPX4 loss. These efforts uncovered the flavoprotein "apoptosis inducing factor mitochondria-associated 2 (AIFM2)" as a previously unrecognized anti-ferroptotic gene. AIFM2, hereafter renamed "ferroptosis-suppressor-protein 1" (FSP1), initially described as a pro-apoptotic gene11, confers an unprecedented protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that ferroptosis suppression by FSP1 is mediated via ubiquinone (CoQ10): its reduced form ubiquinol traps lipid peroxyl radicals that mediate lipid peroxidation, while FSP1 catalyses its regeneration by using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, FSP1/CoQ10/NAD(P)H exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione (GSH) to suppress phospholipid peroxidation (pLPO) and ferroptosis.

Authors+Show Affiliations

Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Germany.University of Würzburg, Rudolf Virchow Center for Experimental Biomedicine, Würzburg, Germany.University of Ottawa, Department of Chemistry & Biomolecular Sciences, Ottawa, Ontario, Canada.Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, UK.Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Germany.Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Germany.Imperial College London, Department of Chemistry, Molecular Sciences Research Hub, London, UK.University of Würzburg, Rudolf Virchow Center for Experimental Biomedicine, Würzburg, Germany.Helmholtz Zentrum München, Institute of Stem Cell Biology, Neuherberg, Germany.Helmholtz Zentrum München, Institute of Stem Cell Biology, Neuherberg, Germany.Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Germany.Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Germany.Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Germany.Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Germany.Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Germany.Helmholtz Zentrum München, Institute of Lung Biology and Disease, Neuherberg, Germany.Helmholtz Zentrum München, Monoclonal Antibody Core Facility, Neuherberg, Germany.Helmholtz Zentrum München, Monoclonal Antibody Core Facility, Neuherberg, Germany.Department of Biotechnology & Biophysics, Biocenter, Julius Maximilian University of Würzburg, Würzburg, Germany.Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, UK.Department of Biotechnology & Biophysics, Biocenter, Julius Maximilian University of Würzburg, Würzburg, Germany.Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.Imperial College London, Department of Chemistry, Molecular Sciences Research Hub, London, UK.Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, Würzburg, Germany.Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, Würzburg, Germany.Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, UK.Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Germany.Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.University of Ottawa, Department of Chemistry & Biomolecular Sciences, Ottawa, Ontario, Canada.University of Würzburg, Rudolf Virchow Center for Experimental Biomedicine, Würzburg, Germany. pedro.angeli@virchow.uni-wuerzburg.de.Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Germany. marcus.conrad@helmholtz-muenchen.de.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31634899

Citation

Doll, Sebastian, et al. "FSP1 Is a Glutathione-independent Ferroptosis Suppressor." Nature, 2019.
Doll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019.
Doll, S., Freitas, F. P., Shah, R., Aldrovandi, M., da Silva, M. C., Ingold, I., ... Conrad, M. (2019). FSP1 is a glutathione-independent ferroptosis suppressor. Nature, doi:10.1038/s41586-019-1707-0.
Doll S, et al. FSP1 Is a Glutathione-independent Ferroptosis Suppressor. Nature. 2019 Oct 21; PubMed PMID: 31634899.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FSP1 is a glutathione-independent ferroptosis suppressor. AU - Doll,Sebastian, AU - Freitas,Florencio Porto, AU - Shah,Ron, AU - Aldrovandi,Maceler, AU - da Silva,Milene Costa, AU - Ingold,Irina, AU - Grocin,Andrea Goya, AU - Xavier da Silva,Thamara Nishida, AU - Panzilius,Elena, AU - Scheel,Christina, AU - Mourão,André, AU - Buday,Katalin, AU - Sato,Mami, AU - Wanninger,Jonas, AU - Vignane,Thibaut, AU - Mohana,Vaishnavi, AU - Rehberg,Markus, AU - Flatley,Andrew, AU - Schepers,Aloys, AU - Kurz,Andreas, AU - White,Daniel, AU - Sauer,Markus, AU - Sattler,Michael, AU - Tate,Edward William, AU - Schmitz,Werner, AU - Schulze,Almut, AU - O'Donnel,Valerie, AU - Proneth,Bettina, AU - Popowicz,Grzegorz M, AU - Pratt,Derek, AU - Angeli,José Pedro Friedmann, AU - Conrad,Marcus, Y1 - 2019/10/21/ PY - 2019/02/25/received PY - 2019/10/09/accepted PY - 2019/10/22/entrez PY - 2019/10/22/pubmed PY - 2019/10/22/medline JF - Nature JO - Nature N2 - Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids1,2. To date, ferroptosis has been believed to be restrained only by the phospholipid hydroperoxide (PLOOH)-reducing enzyme glutathione peroxidase 4 (GPX4)3,4 and radical-trapping antioxidants (RTAs)5,6. The factors which underlie a given cell type's sensitivity to ferroptosis7 are, however, critical to understand the pathophysiological role of ferroptosis and how it may be exploited for cancer treatment. Although metabolic constraints8 and phospholipid composition9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been yet been identified that account for ferroptosis resistance. We undertook an expression cloning approach to identify genes able to complement GPX4 loss. These efforts uncovered the flavoprotein "apoptosis inducing factor mitochondria-associated 2 (AIFM2)" as a previously unrecognized anti-ferroptotic gene. AIFM2, hereafter renamed "ferroptosis-suppressor-protein 1" (FSP1), initially described as a pro-apoptotic gene11, confers an unprecedented protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that ferroptosis suppression by FSP1 is mediated via ubiquinone (CoQ10): its reduced form ubiquinol traps lipid peroxyl radicals that mediate lipid peroxidation, while FSP1 catalyses its regeneration by using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, FSP1/CoQ10/NAD(P)H exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione (GSH) to suppress phospholipid peroxidation (pLPO) and ferroptosis. SN - 1476-4687 UR - https://www.unboundmedicine.com/medline/citation/31634899/FSP1_is_a_glutathione-independent_ferroptosis_suppressor L2 - https://doi.org/10.1038/s41586-019-1707-0 DB - PRIME DP - Unbound Medicine ER -