{{Short description|Protein-coding gene in the species Homo sapiens}} {{cs1 config|name-list-style=vanc}} {{Infobox_gene}} '''Apoptosis-inducing factor 2''' (AIFM2), also known as ferroptosis suppressor protein 1 (FSP1), apoptosis-inducing factor-homologous mitochondrion-associated inducer of death (AMID), is a protein that in humans is encoded by the ''AIFM2'' gene, also known as p53-responsive gene 3 (PRG3), on chromosome 10.<ref name="pmid12135761">{{cite journal | vauthors = Ohiro Y, Garkavtsev I, Kobayashi S, Sreekumar KR, Nantz R, Higashikubo BT, Duffy SL, Higashikubo R, Usheva A, Gius D, Kley N, Horikoshi N | title = A novel p53-inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis-inducing factor (AIF) | journal = FEBS Letters | volume = 524 | issue = 1–3 | pages = 163–71 | date = July 2002 | pmid = 12135761 | doi = 10.1016/S0014-5793(02)03049-1 | s2cid = 6972218 | doi-access = free | bibcode = 2002FEBSL.524..163O }}</ref><ref name="pmid11980907">{{cite journal | vauthors = Wu M, Xu LG, Li X, Zhai Z, Shu HB | title = AMID, an apoptosis-inducing factor-homologous mitochondrion-associated protein, induces caspase-independent apoptosis | journal = The Journal of Biological Chemistry | volume = 277 | issue = 28 | pages = 25617–23 | date = July 2002 | pmid = 11980907 | doi = 10.1074/jbc.M202285200 | doi-access = free }}</ref><ref name="pmid15958387">{{cite journal | vauthors = Marshall KR, Gong M, Wodke L, Lamb JH, Jones DJ, Farmer PB, Scrutton NS, Munro AW | title = The human apoptosis-inducing protein AMID is an oxidoreductase with a modified flavin cofactor and DNA binding activity | journal = The Journal of Biological Chemistry | volume = 280 | issue = 35 | pages = 30735–40 | date = September 2005 | pmid = 15958387 | doi = 10.1074/jbc.M414018200 | doi-access = free }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: AIFM2 apoptosis-inducing factor, mitochondrion-associated, 2| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=84883}}</ref><ref name="Doll_2019">{{cite journal | vauthors = Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, Goya Grocin A, Xavier da Silva TN, Panzilius E, Scheel CH, Mourão A, Buday K, Sato M, Wanninger J, Vignane T, Mohana V, Rehberg M, Flatley A, Schepers A, Kurz A, White D, Sauer M, Sattler M, Tate EW, Schmitz W, Schulze A, O'Donnell V, Proneth B, Popowicz GM, Pratt DA, Angeli JP, Conrad M | display-authors = 6 | title = FSP1 is a glutathione-independent ferroptosis suppressor | journal = Nature | volume = 575 | issue = 7784 | pages = 693–698 | date = November 2019 | pmid = 31634899 | doi = 10.1038/s41586-019-1707-0 | bibcode = 2019Natur.575..693D | hdl = 10044/1/75345 | s2cid = 204833583 | url = https://orca.cardiff.ac.uk/id/eprint/126674/ | hdl-access = free }}</ref><ref name="Bersuker_2019">{{cite journal | vauthors = Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, Roberts MA, Tong B, Maimone TJ, Zoncu R, Bassik MC, Nomura DK, Dixon SJ, Olzmann JA | display-authors = 6 | title = The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis | journal = Nature | volume = 575 | issue = 7784 | pages = 688–692 | date = November 2019 | pmid = 31634900 | pmc = 6883167 | doi = 10.1038/s41586-019-1705-2 | bibcode = 2019Natur.575..688B }}</ref>
This gene encodes a flavoprotein oxidoreductase that reduces coenzyme Q10, vitamin E, and vitamin K.
== Function ==
The AIFM2 gene encodes the FSP1 protein encoded by this gene has significant homology to NADH oxidoreductases and the apoptosis-inducing factor PDCD8/AIF. Although it was originally proposed that this protein induce apoptosis due to its similarity with AIF, findings from James Olzmann's group at UC Berkeley <ref name="Bersuker_2019" /> and Marcus Conrad's group at the Helmholtz Institute <ref name="Doll_2019" /> demonstrated that the primary cellular function of FSP1 is to suppress lipid peroxidation and the induction of the regulated, non-apoptotic cell death pathway known as ferroptosis. Mechanistically, FSP1 reduces oxidized coenzyme Q10 (i.e., ubiquinone) to its reduced form (i.e., ubiquinol), which functions as an excellent lipophilic antioxidant to prevent the propagation of lipid peroxidation.<ref name="Doll_2019" /><ref name="Bersuker_2019" /> FSP1 also may act through the reduction of other molecules that function as radical trapping antioxidants, such as vitamin E and vitamin K<ref>{{Cite journal |last=Jin |first=Da-Yun |last2=Chen |first2=Xuejie |last3=Liu |first3=Yizhou |last4=Williams |first4=Craig M. |last5=Pedersen |first5=Lars C. |last6=Stafford |first6=Darrel W. |last7=Tie |first7=Jian-Ke |date=2023-02-14 |title=A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase |url=https://www.nature.com/articles/s41467-023-36446-8 |journal=Nature Communications |language=en |volume=14 |issue=1 |doi=10.1038/s41467-023-36446-8 |issn=2041-1723 |pmc=9929328 |pmid=36788244}}</ref><ref>{{Cite journal |last=Mishima |first=Eikan |last2=Ito |first2=Junya |last3=Wu |first3=Zijun |last4=Nakamura |first4=Toshitaka |last5=Wahida |first5=Adam |last6=Doll |first6=Sebastian |last7=Tonnus |first7=Wulf |last8=Nepachalovich |first8=Palina |last9=Eggenhofer |first9=Elke |last10=Aldrovandi |first10=Maceler |last11=Henkelmann |first11=Bernhard |last12=Yamada |first12=Ken-ichi |last13=Wanninger |first13=Jonas |last14=Zilka |first14=Omkar |last15=Sato |first15=Emiko |date=2022-08-25 |title=A non-canonical vitamin K cycle is a potent ferroptosis suppressor |url=https://www.nature.com/articles/s41586-022-05022-3 |journal=Nature |language=en |volume=608 |issue=7924 |pages=778–783 |doi=10.1038/s41586-022-05022-3 |issn=0028-0836 |pmc=9402432 |pmid=35922516}}</ref>. FSP1 acts both at the plasma membrane and at internal organelle membranes, such as at lipid droplets where it protects stored neutral lipids<ref>{{Cite journal |last=Lange |first=Mike |last2=Wölk |first2=Michele |last3=Li |first3=Vivian Wen |last4=Doubravsky |first4=Cody E. |last5=Hendricks |first5=Joseph M. |last6=Kato |first6=Shunji |last7=Otoki |first7=Yurika |last8=Styler |first8=Benjamin |last9=Johnson |first9=Sean L. |last10=Harris |first10=Cynthia A. |last11=Nakagawa |first11=Kiyotaka |last12=Snodgrass |first12=Isabel F. |last13=Kim |first13=Dohee |last14=Newman |first14=John W. |last15=Fedorova |first15=Maria |date=November 2025 |title=FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis |url=https://www.nature.com/articles/s41556-025-01790-y |journal=Nature Cell Biology |language=en |volume=27 |issue=11 |pages=1902–1913 |doi=10.1038/s41556-025-01790-y |issn=1465-7392 |pmc=12611765 |pmid=41162632}}</ref>.
== Structure ==
AIFM2 can be found only both in prokaryotes and eukaryotes.<ref name="pmid11980907"/><ref name="pmid15958387"/><ref name="Klim 2121–2134">{{cite journal | vauthors = Klim J, Gładki A, Kucharczyk R, Zielenkiewicz U, Kaczanowski S | title = Ancestral State Reconstruction of the Apoptosis Machinery in the Common Ancestor of Eukaryotes | journal = G3 | volume = 8 | issue = 6 | pages = 2121–2134 | date = May 2018 | pmid = 29703784 | pmc = 5982838 | doi = 10.1534/g3.118.200295 }}</ref><ref name=pmid15273740>{{cite journal | vauthors = Wu M, Xu LG, Su T, Tian Y, Zhai Z, Shu HB | title = AMID is a p53-inducible gene downregulated in tumors | journal = Oncogene | volume = 23 | issue = 40 | pages = 6815–9 | date = September 2004 | pmid = 15273740 | doi = 10.1038/sj.onc.1207909 | doi-access = | s2cid = 8541615 }}</ref> Sequence analysis reveals that the ''AIFM2'' gene promoter contains a consensus transcription initiator sequence instead of a TATA box.<ref name=pmid15273740/> Though AIFM2 also lacks a recognizable mitochondrial localization sequence and cannot enter the mitochondria, it is found to adhere to the outer mitochondrial membrane (OMM), where it forms a ring-like structure.<ref name="pmid11980907"/><ref name=pmid12135761/><ref name="pmid15958387"/><ref name=pmid15273740/><ref name="pmid17711848">{{cite journal |vauthors=Gong M, Hay S, Marshall KR, Munro AW, Scrutton NS |date=October 2007 |title=DNA binding suppresses human AIF-M2 activity and provides a connection between redox chemistry, reactive oxygen species, and apoptosis |journal=The Journal of Biological Chemistry |volume=282 |issue=41 |pages=30331–40 |doi=10.1074/jbc.m703713200 |pmid=17711848 |doi-access=free}}</ref> Two deletion mutations at the N-terminal (aa 1–185 and 1–300) result in nuclear localization and failure to effect cell death, suggesting that AIFM2 must be associated with the mitochondria in order to induce apoptosis. Moreover, domain mapping experiments reveal that only the C-terminal 187 aa is required for apoptotic induction.<ref name="pmid11980907"/> Meanwhile, mutations in the N-terminal putative FAD- and ADP-binding domains, which are responsible for its oxidoreductase function, do not affect its apoptotic function, thus indicating that these two functions operate independently.<ref name="pmid15958387"/><ref name=pmid12135761 /> It assembles stoichiometrically and noncovalently with 6-hydroxy-FAD.<ref name="pmid15958387"/>
The ''AIFM2'' gene contains a putative p53-binding element in intron 5, suggesting that its gene expression can be activated by p53.<ref name=pmid12135761/><ref name="pmid15958387"/><ref name=pmid15273740/>
== Clinical significance ==
FSP1 is upregulated in several cancers and its upregulation correlates with poor prognosis. FSP1 is a NRF2 targeted gene and contributes to NRF2-dependent ferroptosis resistance. Loss of FSP1 in preclinical mouse models results in a reduction in tumor growth<ref>{{Cite journal |last=Wu |first=Katherine |last2=Vaughan |first2=Alec J. |last3=Bossowski |first3=Jozef P. |last4=Hao |first4=Yuan |last5=Ziogou |first5=Aikaterini |last6=Kim |first6=Seon Min |last7=Kim |first7=Tae Ha |last8=Nakamura |first8=Mari N. |last9=Pillai |first9=Ray |last10=Mancini |first10=Mariana |last11=Rajalingam |first11=Sahith |last12=Han |first12=Mingqi |last13=Nakamura |first13=Toshitaka |last14=Wang |first14=Lidong |last15=Chung |first15=Suckwoo |date=January 2026 |title=Targeting FSP1 triggers ferroptosis in lung cancer |url=https://pubmed.ncbi.nlm.nih.gov/41193800 |journal=Nature |volume=649 |issue=8096 |pages=487–495 |doi=10.1038/s41586-025-09710-8 |issn=1476-4687 |pmid=41193800|doi-access=free }}</ref><ref>{{Cite journal |last=Palma |first=Mario |last2=Chaufan |first2=Milena |last3=Breuer |first3=Cort B. |last4=Müller |first4=Sebastian |last5=Sabatier |first5=Marie |last6=Fraser |first6=Cameron S. |last7=Szylo |first7=Krystina J. |last8=Yavari |first8=Mahsa |last9=Carmona |first9=Alanis |last10=Kaur |first10=Mayher |last11=Melo |first11=Luiza Martins Nascentes |last12=Cansiz |first12=Feyza |last13=Monge-Lorenzo |first13=June |last14=Flores |first14=Midori |last15=Mishima |first15=Eikan |date=2026-01-08 |title=Lymph node environment drives FSP1 targetability in metastasizing melanoma |url=https://www.nature.com/articles/s41586-025-09709-1 |journal=Nature |language=en |volume=649 |issue=8096 |pages=477–486 |doi=10.1038/s41586-025-09709-1 |issn=0028-0836 |pmc=12779575 |pmid=41193799}}</ref>. Inhibitors<ref name="Doll_2019" /><ref>{{cite journal |last1=Nakamura |first1=Toshitaka |last2=Hipp |first2=Clara |last3=Santos Dias Mourão |first3=André |last4=Borggräfe |first4=Jan |last5=Aldrovandi |first5=Maceler |last6=Henkelmann |first6=Bernhard |last7=Wanninger |first7=Jonas |last8=Mishima |first8=Eikan |last9=Lytton |first9=Elena |last10=Emler |first10=David |last11=Proneth |first11=Bettina |last12=Sattler |first12=Michael |last13=Conrad |first13=Marcus |date=July 2023 |title=Phase separation of FSP1 promotes ferroptosis |journal=Nature |language=en |volume=619 |issue=7969 |pages=371–377 |doi=10.1038/s41586-023-06255-6 |pmid=37380771 |issn=1476-4687|pmc=10338336 |bibcode=2023Natur.619..371N }}</ref> of FSP1 have been identified to induce or sensitize cells to ferroptosis. icFSP1 has been shown to cause dissociation of FSP1 from the membrane and phase separation of FSP1 into droplets<ref>{{Cite journal |last=Nakamura |first=Toshitaka |last2=Hipp |first2=Clara |last3=Santos Dias Mourão |first3=André |last4=Borggräfe |first4=Jan |last5=Aldrovandi |first5=Maceler |last6=Henkelmann |first6=Bernhard |last7=Wanninger |first7=Jonas |last8=Mishima |first8=Eikan |last9=Lytton |first9=Elena |last10=Emler |first10=David |last11=Proneth |first11=Bettina |last12=Sattler |first12=Michael |last13=Conrad |first13=Marcus |date=2023-07-13 |title=Phase separation of FSP1 promotes ferroptosis |url=https://www.nature.com/articles/s41586-023-06255-6 |journal=Nature |language=en |volume=619 |issue=7969 |pages=371–377 |doi=10.1038/s41586-023-06255-6 |issn=0028-0836 |pmc=10338336 |pmid=37380771}}</ref>. More commonly used FSP1 inhibitors include FSEN1<ref>{{Cite journal |last=Hendricks |first=Joseph M. |last2=Doubravsky |first2=Cody E. |last3=Wehri |first3=Eddie |last4=Li |first4=Zhipeng |last5=Roberts |first5=Melissa A. |last6=Deol |first6=Kirandeep K. |last7=Lange |first7=Mike |last8=Lasheras-Otero |first8=Irene |last9=Momper |first9=Jeremiah D. |last10=Dixon |first10=Scott J. |last11=Bersuker |first11=Kirill |last12=Schaletzky |first12=Julia |last13=Olzmann |first13=James A. |date=September 2023 |title=Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis |url=https://linkinghub.elsevier.com/retrieve/pii/S2451945623001149 |journal=Cell Chemical Biology |language=en |volume=30 |issue=9 |pages=1090–1103.e7 |doi=10.1016/j.chembiol.2023.04.007 |pmc=10524360 |pmid=37178691}}</ref><ref>{{Cite journal |last=Zhang |first=Sitao |last2=Megarioti |first2=Amalia H. |last3=Hendricks |first3=Joseph M. |last4=Zhou |first4=Junshu |last5=Sun |first5=Qingxiang |last6=Jia |first6=Da |last7=Olzmann |first7=James A. |date=2025-06-03 |title=Cocrystal structure reveals the mechanism of FSP1 inhibition by FSEN1 |url=https://pnas.org/doi/10.1073/pnas.2505197122 |journal=Proceedings of the National Academy of Sciences |language=en |volume=122 |issue=22 |doi=10.1073/pnas.2505197122 |issn=0027-8424 |pmc=12146761 |pmid=40440064}}</ref> and iFSP1<ref name="Doll_2019" />, which are both direct competitive inhibitors that are selective to human FSP1. Whether FSP1 is an important therapeutic target remains to be determined.
== Evolution == The phylogenetic studies indicates that the divergence of the AIFM1 and other AIFs occurred before the divergence of eukaryotes.<ref name="Klim 2121–2134"/>
== Interactions ==
AIFM2 is shown to interact with p53.<ref name=pmid12135761/>
AIFM2 is not inhibited by Bcl-2.<ref name=pmid12135761/>
AIFM2 can also bind the following coenzymes: *6-hydroxy-FAD,<ref name="pmid15958387"/> *Flavin adenine dinucleotide (FAD),<ref name="pmid15958387"/> *NADPH/NADP+,<ref name="pmid15958387"/> *NADH/NAD+,<ref name="pmid15958387"/> and *pyridine nucleotide coenzyme.<ref name="pmid15958387"/>
== References == {{reflist}}
== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = Horikoshi N, Cong J, Kley N, Shenk T | title = Isolation of differentially expressed cDNAs from p53-dependent apoptotic cells: activation of the human homologue of the Drosophila peroxidasin gene | journal = Biochemical and Biophysical Research Communications | volume = 261 | issue = 3 | pages = 864–9 | date = August 1999 | pmid = 10441517 | doi = 10.1006/bbrc.1999.1123 | bibcode = 1999BBRC..261..864H }} * {{cite journal | vauthors = Zhang W, Li D, Mehta JL | title = Role of AIF in human coronary artery endothelial cell apoptosis | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 286 | issue = 1 | pages = H354-8 | date = January 2004 | pmid = 14684364 | doi = 10.1152/ajpheart.00579.2003 }} * {{cite journal | vauthors = Wu M, Xu LG, Su T, Tian Y, Zhai Z, Shu HB | title = AMID is a p53-inducible gene downregulated in tumors | journal = Oncogene | volume = 23 | issue = 40 | pages = 6815–9 | date = September 2004 | pmid = 15273740 | doi = 10.1038/sj.onc.1207909 | doi-access = | s2cid = 8541615 }} * {{cite journal | vauthors = Varecha M, Amrichová J, Zimmermann M, Ulman V, Lukásová E, Kozubek M | title = Bioinformatic and image analyses of the cellular localization of the apoptotic proteins endonuclease G, AIF, and AMID during apoptosis in human cells | journal = Apoptosis | volume = 12 | issue = 7 | pages = 1155–71 | date = July 2007 | pmid = 17347867 | doi = 10.1007/s10495-007-0061-0 | s2cid = 29846503 }} * {{cite journal | vauthors = Gong M, Hay S, Marshall KR, Munro AW, Scrutton NS | title = DNA binding suppresses human AIF-M2 activity and provides a connection between redox chemistry, reactive oxygen species, and apoptosis | journal = The Journal of Biological Chemistry | volume = 282 | issue = 41 | pages = 30331–40 | date = October 2007 | pmid = 17711848 | doi = 10.1074/jbc.M703713200 | doi-access = free}} {{refend}}
== External links == * {{UCSC gene info|AIFM2}} * {{UCSC gene info|PRG3}}
Category:Proteins