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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 |
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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 |
format | article |
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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.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-019-1707-0</identifier><identifier>PMID: 31634899</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>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</subject><ispartof>Nature (London), 2019-11, Vol.575 (7784), p.693-698</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2019</rights><rights>COPYRIGHT 2019 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Nov 28, 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c618t-21e0b35a2d9c8ac424ce18f6ed502d482d8fe9541bcde5112d8db65006da75ee3</citedby><cites>FETCH-LOGICAL-c618t-21e0b35a2d9c8ac424ce18f6ed502d482d8fe9541bcde5112d8db65006da75ee3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31634899$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Doll, Sebastian</creatorcontrib><creatorcontrib>Freitas, Florencio Porto</creatorcontrib><creatorcontrib>Shah, Ron</creatorcontrib><creatorcontrib>Aldrovandi, Maceler</creatorcontrib><creatorcontrib>da Silva, Milene Costa</creatorcontrib><creatorcontrib>Ingold, Irina</creatorcontrib><creatorcontrib>Goya Grocin, Andrea</creatorcontrib><creatorcontrib>Xavier da Silva, Thamara Nishida</creatorcontrib><creatorcontrib>Panzilius, Elena</creatorcontrib><creatorcontrib>Scheel, Christina H.</creatorcontrib><creatorcontrib>Mourão, André</creatorcontrib><creatorcontrib>Buday, Katalin</creatorcontrib><creatorcontrib>Sato, Mami</creatorcontrib><creatorcontrib>Wanninger, Jonas</creatorcontrib><creatorcontrib>Vignane, Thibaut</creatorcontrib><creatorcontrib>Mohana, Vaishnavi</creatorcontrib><creatorcontrib>Rehberg, Markus</creatorcontrib><creatorcontrib>Flatley, Andrew</creatorcontrib><creatorcontrib>Schepers, Aloys</creatorcontrib><creatorcontrib>Kurz, Andreas</creatorcontrib><creatorcontrib>White, Daniel</creatorcontrib><creatorcontrib>Sauer, Markus</creatorcontrib><creatorcontrib>Sattler, Michael</creatorcontrib><creatorcontrib>Tate, Edward William</creatorcontrib><creatorcontrib>Schmitz, Werner</creatorcontrib><creatorcontrib>Schulze, Almut</creatorcontrib><creatorcontrib>O’Donnell, Valerie</creatorcontrib><creatorcontrib>Proneth, Bettina</creatorcontrib><creatorcontrib>Popowicz, Grzegorz M.</creatorcontrib><creatorcontrib>Pratt, Derek A.</creatorcontrib><creatorcontrib>Angeli, José Pedro Friedmann</creatorcontrib><creatorcontrib>Conrad, Marcus</creatorcontrib><title>FSP1 is a glutathione-independent ferroptosis suppressor</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><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.</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 & derivatives</subject><subject>Ubiquinone - metabolism</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp10lFrFDEQB_Agir1WP4AvcuhLfUidySbZ7GMprRYKLVafQy6ZXbfs7W6TXajfvjmuWk9OFrIk-c0Qhj9j7xBOEArzOUlURnPAimMJJYcXbIGy1FxqU75kCwBhOJhCH7DDlO4AQGEpX7ODAnUhTVUtmLm4vcFlm5Zu2XTz5Kaf7dATb_tAI-Wln5Y1xTiM05CySvM4RkppiG_Yq9p1id4-_Y_Yj4vz72df-dX1l8uz0yvuNZqJCyRYFcqJUHnjvBTSE5paU1AggjQimJoqJXHlAynEvA8rrQB0cKUiKo7Y8bbvGIf7mdJk123y1HWup2FOVhRQlqKqUGb68R96N8yxz6_LSqA2WinxrBrXkW37epii85um9lSLohQgdZUV36Ma6im6Lk-obvPxjv-wx_uxvbd_o5M9KH-B1q3f2_XTTkE2Ez1MjZtTspe333Ytbq2PQ0qRajvGdu3iL4tgN3Gx27jYHBe7iYuFXPP-aWLzak3hT8XvfGQgtiDlq76h-DzS_3d9BKWTxVg</recordid><startdate>201911</startdate><enddate>201911</enddate><creator>Doll, Sebastian</creator><creator>Freitas, Florencio Porto</creator><creator>Shah, Ron</creator><creator>Aldrovandi, Maceler</creator><creator>da Silva, Milene Costa</creator><creator>Ingold, Irina</creator><creator>Goya Grocin, Andrea</creator><creator>Xavier da Silva, Thamara Nishida</creator><creator>Panzilius, Elena</creator><creator>Scheel, Christina H.</creator><creator>Mourão, André</creator><creator>Buday, Katalin</creator><creator>Sato, Mami</creator><creator>Wanninger, Jonas</creator><creator>Vignane, Thibaut</creator><creator>Mohana, Vaishnavi</creator><creator>Rehberg, Markus</creator><creator>Flatley, Andrew</creator><creator>Schepers, Aloys</creator><creator>Kurz, Andreas</creator><creator>White, Daniel</creator><creator>Sauer, Markus</creator><creator>Sattler, Michael</creator><creator>Tate, Edward William</creator><creator>Schmitz, Werner</creator><creator>Schulze, Almut</creator><creator>O’Donnell, Valerie</creator><creator>Proneth, Bettina</creator><creator>Popowicz, Grzegorz M.</creator><creator>Pratt, Derek A.</creator><creator>Angeli, José Pedro Friedmann</creator><creator>Conrad, Marcus</creator><general>Nature Publishing Group UK</general><general>Nature Publishing 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is a glutathione-independent ferroptosis suppressor</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c618t-21e0b35a2d9c8ac424ce18f6ed502d482d8fe9541bcde5112d8db65006da75ee3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>13/1</topic><topic>13/106</topic><topic>13/31</topic><topic>14/19</topic><topic>631/45/608</topic><topic>631/80/82</topic><topic>Analysis</topic><topic>Animals</topic><topic>Antioxidants</topic><topic>Apoptosis</topic><topic>Apoptosis Regulatory Proteins - genetics</topic><topic>Apoptosis Regulatory Proteins - metabolism</topic><topic>Apoptosis-inducing factor</topic><topic>Apoptotic proteins</topic><topic>Cancer</topic><topic>Cell death</topic><topic>Cell Line, Tumor</topic><topic>Clonal deletion</topic><topic>Cloning</topic><topic>Coenzyme Q10</topic><topic>Composition</topic><topic>Control</topic><topic>Enzymes</topic><topic>Ferroptosis</topic><topic>Ferroptosis - genetics</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Knockout Techniques</topic><topic>Glutathione</topic><topic>Glutathione - metabolism</topic><topic>Glutathione peroxidase</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Iron</topic><topic>Lipid peroxidation</topic><topic>Lipid Peroxidation - genetics</topic><topic>Lipids</topic><topic>Localization</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Mitochondria</topic><topic>Mitochondrial Proteins - genetics</topic><topic>Mitochondrial Proteins - metabolism</topic><topic>multidisciplinary</topic><topic>NAD</topic><topic>Oxidative stress</topic><topic>Peroxidase</topic><topic>Peroxidation</topic><topic>Peroxyl radicals</topic><topic>Phospholipids</topic><topic>Proteins</topic><topic>Regeneration</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Sensitivity</topic><topic>Ubiquinol</topic><topic>Ubiquinone</topic><topic>Ubiquinone - analogs & derivatives</topic><topic>Ubiquinone - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Doll, Sebastian</creatorcontrib><creatorcontrib>Freitas, Florencio Porto</creatorcontrib><creatorcontrib>Shah, Ron</creatorcontrib><creatorcontrib>Aldrovandi, Maceler</creatorcontrib><creatorcontrib>da Silva, Milene Costa</creatorcontrib><creatorcontrib>Ingold, Irina</creatorcontrib><creatorcontrib>Goya Grocin, Andrea</creatorcontrib><creatorcontrib>Xavier da Silva, Thamara Nishida</creatorcontrib><creatorcontrib>Panzilius, Elena</creatorcontrib><creatorcontrib>Scheel, Christina H.</creatorcontrib><creatorcontrib>Mourão, André</creatorcontrib><creatorcontrib>Buday, Katalin</creatorcontrib><creatorcontrib>Sato, Mami</creatorcontrib><creatorcontrib>Wanninger, Jonas</creatorcontrib><creatorcontrib>Vignane, Thibaut</creatorcontrib><creatorcontrib>Mohana, Vaishnavi</creatorcontrib><creatorcontrib>Rehberg, 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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> |
fulltext | fulltext |
identifier | ISSN: 0028-0836 |
ispartof | Nature (London), 2019-11, Vol.575 (7784), p.693-698 |
issn | 0028-0836 1476-4687 |
language | eng |
recordid | cdi_proquest_miscellaneous_2307729914 |
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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