FSP1 is a glutathione-independent ferroptosis suppressor

Sebastian Doll, Florencio Porto Freitas, Ron Shah, Maceler Aldrovandi, Milene Costa Silva, Irina Ingold, Andrea Goya Grocin, Thamara Nishida Xavier da Silva, Elena Panzilius, Christina H. Scheel, André Mourão, Katalin Buday, Mami Sato, Jonas Wanninger, Thibaut Vignane, Vaishnavi Mohana, Markus Rehberg, Andrew Flatley, Aloys Schepers, Andreas Kurz, Daniel White, Markus Sauer, Michael Sattler, Edward William Tate, Werner Schmitz, Almut Schulze, Valerie O’Donnell, Bettina Proneth, Grzegorz M. Popowicz, Derek A. Pratt, José Pedro Friedmann Angeli () and Marcus Conrad ()
Additional contact information
Sebastian Doll: Institute of Developmental Genetics, Helmholtz Zentrum München
Florencio Porto Freitas: University of Würzburg
Ron Shah: University of Ottawa
Maceler Aldrovandi: Institute of Developmental Genetics, Helmholtz Zentrum München
Milene Costa Silva: Institute of Developmental Genetics, Helmholtz Zentrum München
Irina Ingold: Institute of Developmental Genetics, Helmholtz Zentrum München
Andrea Goya Grocin: Imperial College London
Thamara Nishida Xavier da Silva: University of Würzburg
Elena Panzilius: Institute of Stem Cell Biology, Helmholtz Zentrum München
Christina H. Scheel: Institute of Stem Cell Biology, Helmholtz Zentrum München
André Mourão: Institute of Structural Biology, Helmholtz Zentrum München
Katalin Buday: Institute of Developmental Genetics, Helmholtz Zentrum München
Mami Sato: Institute of Developmental Genetics, Helmholtz Zentrum München
Jonas Wanninger: Institute of Developmental Genetics, Helmholtz Zentrum München
Thibaut Vignane: Institute of Developmental Genetics, Helmholtz Zentrum München
Vaishnavi Mohana: Institute of Developmental Genetics, Helmholtz Zentrum München
Markus Rehberg: Institute of Lung Biology and Disease, Helmholtz Zentrum München
Andrew Flatley: Helmholtz Zentrum München
Aloys Schepers: Helmholtz Zentrum München
Andreas Kurz: Biocenter, University of Würzburg
Daniel White: Systems Immunity Research Institute, School of Medicine, Cardiff University
Markus Sauer: Biocenter, University of Würzburg
Michael Sattler: Institute of Structural Biology, Helmholtz Zentrum München
Edward William Tate: Imperial College London
Werner Schmitz: Theodor Boveri Institute, Biocenter, University of Würzburg
Almut Schulze: Theodor Boveri Institute, Biocenter, University of Würzburg
Valerie O’Donnell: Systems Immunity Research Institute, School of Medicine, Cardiff University
Bettina Proneth: Institute of Developmental Genetics, Helmholtz Zentrum München
Grzegorz M. Popowicz: Institute of Structural Biology, Helmholtz Zentrum München
Derek A. Pratt: University of Ottawa
José Pedro Friedmann Angeli: University of Würzburg
Marcus Conrad: Institute of Developmental Genetics, Helmholtz Zentrum München

Nature, 2019, vol. 575, issue 7784, 693-698

Abstract: Abstract Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids1,2. To date, ferroptosis has been thought to be controlled only by the phospholipid hydroperoxide-reducing enzyme glutathione peroxidase 4 (GPX4)3,4 and radical-trapping antioxidants5,6. However, elucidation of the factors that underlie the sensitivity of a given cell type to ferroptosis7 is crucial to understand the pathophysiological role of ferroptosis and how it may be exploited for the treatment of cancer. Although metabolic constraints8 and phospholipid composition9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been identified that account for the resistance of cells to ferroptosis. Here we used an expression cloning approach to identify genes in human cancer cells that are able to complement the loss of GPX4. We found that the flavoprotein apoptosis-inducing factor mitochondria-associated 2 (AIFM2) is a previously unrecognized anti-ferroptotic gene. AIFM2, which we renamed ferroptosis suppressor protein 1 (FSP1) and which was initially described as a pro-apoptotic gene11, confers protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that the suppression of ferroptosis by FSP1 is mediated by ubiquinone (also known as coenzyme Q10, CoQ10): the reduced form, ubiquinol, traps lipid peroxyl radicals that mediate lipid peroxidation, whereas FSP1 catalyses the regeneration of CoQ10 using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, the FSP1–CoQ10–NAD(P)H pathway exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione to suppress phospholipid peroxidation and ferroptosis.

Date: 2019
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DOI: 10.1038/s41586-019-1707-0

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