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FSP1 is a glutathione-independent ferroptosis suppressor

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...

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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
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container_title Nature (London)
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creator 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
description 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.
doi_str_mv 10.1038/s41586-019-1707-0
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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. 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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.</description><subject>13/1</subject><subject>13/106</subject><subject>13/31</subject><subject>14/19</subject><subject>631/45/608</subject><subject>631/80/82</subject><subject>Analysis</subject><subject>Animals</subject><subject>Antioxidants</subject><subject>Apoptosis</subject><subject>Apoptosis Regulatory Proteins - genetics</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Apoptosis-inducing factor</subject><subject>Apoptotic proteins</subject><subject>Cancer</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Clonal deletion</subject><subject>Cloning</subject><subject>Coenzyme Q10</subject><subject>Composition</subject><subject>Control</subject><subject>Enzymes</subject><subject>Ferroptosis</subject><subject>Ferroptosis - genetics</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Knockout Techniques</subject><subject>Glutathione</subject><subject>Glutathione - metabolism</subject><subject>Glutathione peroxidase</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Iron</subject><subject>Lipid peroxidation</subject><subject>Lipid Peroxidation - genetics</subject><subject>Lipids</subject><subject>Localization</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mitochondria</subject><subject>Mitochondrial Proteins - genetics</subject><subject>Mitochondrial Proteins - metabolism</subject><subject>multidisciplinary</subject><subject>NAD</subject><subject>Oxidative stress</subject><subject>Peroxidase</subject><subject>Peroxidation</subject><subject>Peroxyl radicals</subject><subject>Phospholipids</subject><subject>Proteins</subject><subject>Regeneration</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Sensitivity</subject><subject>Ubiquinol</subject><subject>Ubiquinone</subject><subject>Ubiquinone - analogs &amp; 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Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Earth, Atmospheric &amp; Aquatic Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>University of Michigan</collection><collection>Genetics Abstracts</collection><collection>SIRS Editorial</collection><collection>Environment Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Doll, Sebastian</au><au>Freitas, Florencio Porto</au><au>Shah, Ron</au><au>Aldrovandi, Maceler</au><au>da Silva, Milene Costa</au><au>Ingold, Irina</au><au>Goya Grocin, Andrea</au><au>Xavier da Silva, Thamara Nishida</au><au>Panzilius, Elena</au><au>Scheel, Christina H.</au><au>Mourão, André</au><au>Buday, Katalin</au><au>Sato, Mami</au><au>Wanninger, Jonas</au><au>Vignane, Thibaut</au><au>Mohana, Vaishnavi</au><au>Rehberg, Markus</au><au>Flatley, Andrew</au><au>Schepers, Aloys</au><au>Kurz, Andreas</au><au>White, Daniel</au><au>Sauer, Markus</au><au>Sattler, Michael</au><au>Tate, Edward William</au><au>Schmitz, Werner</au><au>Schulze, Almut</au><au>O’Donnell, Valerie</au><au>Proneth, Bettina</au><au>Popowicz, Grzegorz M.</au><au>Pratt, Derek A.</au><au>Angeli, José Pedro Friedmann</au><au>Conrad, Marcus</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>FSP1 is a glutathione-independent ferroptosis suppressor</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2019-11</date><risdate>2019</risdate><volume>575</volume><issue>7784</issue><spage>693</spage><epage>698</epage><pages>693-698</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31634899</pmid><doi>10.1038/s41586-019-1707-0</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record>
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identifier ISSN: 0028-0836
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1476-4687
language eng
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source Nature
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
title FSP1 is a glutathione-independent ferroptosis suppressor
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