FSP1 is a glutathione-independent ferroptosis suppressor

• Published in: Nature (London) 2019-11, Vol.575 (7784), p.693-698
• Main Authors: Doll, Sebastian, Freitas, Florencio Porto, Shah, Ron, Aldrovandi, Maceler, da Silva, Milene Costa, Ingold, Irina, Goya Grocin, Andrea, Xavier da Silva, Thamara Nishida, Panzilius, Elena, Scheel, Christina H., Mourão, André, Buday, Katalin, Sato, Mami, Wanninger, Jonas, Vignane, Thibaut, Mohana, Vaishnavi, Rehberg, Markus, Flatley, Andrew, Schepers, Aloys, Kurz, Andreas, White, Daniel, Sauer, Markus, Sattler, Michael, Tate, Edward William, Schmitz, Werner, Schulze, Almut, O’Donnell, Valerie, Proneth, Bettina, Popowicz, Grzegorz M., Pratt, Derek A., Angeli, José Pedro Friedmann, Conrad, Marcus
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/31; 14/19; 631/45/608; 631/80/82; Analysis; Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Apoptosis-inducing factor; Apoptotic proteins; Cancer; Cell death; Cell Line, Tumor; Clonal deletion; Cloning; Coenzyme Q10; Composition; Control; Enzymes; Ferroptosis; Ferroptosis - genetics; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Glutathione; Glutathione - metabolism; Glutathione peroxidase; Humanities and Social Sciences; Humans; Iron; Lipid peroxidation; Lipid Peroxidation - genetics; Lipids; Localization; Metabolism; Mice; Mitochondria; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; multidisciplinary; NAD; Oxidative stress; Peroxidase; Peroxidation; Peroxyl radicals; Phospholipids; Proteins; Regeneration; Science; Science (multidisciplinary); Sensitivity; Ubiquinol; Ubiquinone; Ubiquinone - analogs & derivatives; Ubiquinone - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1707-0

Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids 1 , 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 antioxidants 5 , 6 . However, elucidation of the factors that underlie the sensitivity of a given cell type to ferroptosis 7 is crucial to understand the pathophysiological role of ferroptosis and how it may be exploited for the treatment of cancer. Although metabolic constraints 8 and phospholipid composition 9 , 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 gene 11 , 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 Q 10 , CoQ 10 ): the reduced form, ubiquinol, traps lipid peroxyl radicals that mediate lipid peroxidation, whereas FSP1 catalyses the regeneration of CoQ 10 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–CoQ 10 –NAD(P)H pathway exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione to suppress phospholipid peroxidation and ferroptosis. In the absence of GPX4, FSP1 regenerates ubiquinol from the oxidized form, ubiquinone, using NAD(P)H and suppresses phospholipid peroxidation and ferroptosis in cells.