Biology:AIFM2

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Short description: Protein-coding gene in the species Homo sapiens

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1][2][3][4][5][6]

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 [6] and Marcus Conrad's group at the Helmholtz Institute [5] 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.[5][6] FSP1 also may act through the reduction of other molecules that function as radical trapping antioxidants, such as vitamin E and vitamin K[7][8]. FSP1 acts both at the plasma membrane and at internal organelle membranes, such as at lipid droplets where it protects stored neutral lipids[9].

Structure

AIFM2 can be found only both in prokaryotes and eukaryotes.[2][3][10][11] Sequence analysis reveals that the AIFM2 gene promoter contains a consensus transcription initiator sequence instead of a TATA box.[11] 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.[2][1][3][11][12] 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.[2] 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.[3][1] It assembles stoichiometrically and noncovalently with 6-hydroxy-FAD.[3]

The AIFM2 gene contains a putative p53-binding element in intron 5, suggesting that its gene expression can be activated by p53.[1][3][11]

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[13][14]. Inhibitors[5][15] 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[16]. More commonly used FSP1 inhibitors include FSEN1[17][18] and iFSP1[5], 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.[10]

Interactions

AIFM2 is shown to interact with p53.[1]

AIFM2 is not inhibited by Bcl-2.[1]

AIFM2 can also bind the following coenzymes:

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "A novel p53-inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis-inducing factor (AIF)". FEBS Letters 524 (1–3): 163–71. July 2002. doi:10.1016/S0014-5793(02)03049-1. PMID 12135761. Bibcode: 2002FEBSL.524..163O. 
  2. ↑ 2.0 2.1 2.2 2.3 "AMID, an apoptosis-inducing factor-homologous mitochondrion-associated protein, induces caspase-independent apoptosis". The Journal of Biological Chemistry 277 (28): 25617–23. July 2002. doi:10.1074/jbc.M202285200. PMID 11980907. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 "The human apoptosis-inducing protein AMID is an oxidoreductase with a modified flavin cofactor and DNA binding activity". The Journal of Biological Chemistry 280 (35): 30735–40. September 2005. doi:10.1074/jbc.M414018200. PMID 15958387. 
  4. ↑ "Entrez Gene: AIFM2 apoptosis-inducing factor, mitochondrion-associated, 2". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=84883. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "FSP1 is a glutathione-independent ferroptosis suppressor". Nature 575 (7784): 693–698. November 2019. doi:10.1038/s41586-019-1707-0. PMID 31634899. Bibcode: 2019Natur.575..693D. https://orca.cardiff.ac.uk/id/eprint/126674/. 
  6. ↑ 6.0 6.1 6.2 "The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis". Nature 575 (7784): 688–692. November 2019. doi:10.1038/s41586-019-1705-2. PMID 31634900. Bibcode: 2019Natur.575..688B. 
  7. ↑ Jin, Da-Yun; Chen, Xuejie; Liu, Yizhou; Williams, Craig M.; Pedersen, Lars C.; Stafford, Darrel W.; Tie, Jian-Ke (2023-02-14). "A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase" (in en). Nature Communications 14 (1). doi:10.1038/s41467-023-36446-8. ISSN 2041-1723. PMID 36788244. PMC 9929328. https://www.nature.com/articles/s41467-023-36446-8. 
  8. ↑ Mishima, Eikan; Ito, Junya; Wu, Zijun; Nakamura, Toshitaka; Wahida, Adam; Doll, Sebastian; Tonnus, Wulf; Nepachalovich, Palina et al. (2022-08-25). "A non-canonical vitamin K cycle is a potent ferroptosis suppressor" (in en). Nature 608 (7924): 778–783. doi:10.1038/s41586-022-05022-3. ISSN 0028-0836. PMID 35922516. PMC 9402432. https://www.nature.com/articles/s41586-022-05022-3. 
  9. ↑ Lange, Mike; Wölk, Michele; Li, Vivian Wen; Doubravsky, Cody E.; Hendricks, Joseph M.; Kato, Shunji; Otoki, Yurika; Styler, Benjamin et al. (November 2025). "FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis" (in en). Nature Cell Biology 27 (11): 1902–1913. doi:10.1038/s41556-025-01790-y. ISSN 1465-7392. PMID 41162632. PMC 12611765. https://www.nature.com/articles/s41556-025-01790-y. 
  10. ↑ 10.0 10.1 "Ancestral State Reconstruction of the Apoptosis Machinery in the Common Ancestor of Eukaryotes". G3 8 (6): 2121–2134. May 2018. doi:10.1534/g3.118.200295. PMID 29703784. 
  11. ↑ 11.0 11.1 11.2 11.3 "AMID is a p53-inducible gene downregulated in tumors". Oncogene 23 (40): 6815–9. September 2004. doi:10.1038/sj.onc.1207909. PMID 15273740. 
  12. ↑ "DNA binding suppresses human AIF-M2 activity and provides a connection between redox chemistry, reactive oxygen species, and apoptosis". The Journal of Biological Chemistry 282 (41): 30331–40. October 2007. doi:10.1074/jbc.m703713200. PMID 17711848. 
  13. ↑ Wu, Katherine; Vaughan, Alec J.; Bossowski, Jozef P.; Hao, Yuan; Ziogou, Aikaterini; Kim, Seon Min; Kim, Tae Ha; Nakamura, Mari N. et al. (January 2026). "Targeting FSP1 triggers ferroptosis in lung cancer". Nature 649 (8096): 487–495. doi:10.1038/s41586-025-09710-8. ISSN 1476-4687. PMID 41193800. https://pubmed.ncbi.nlm.nih.gov/41193800. 
  14. ↑ Palma, Mario; Chaufan, Milena; Breuer, Cort B.; Müller, Sebastian; Sabatier, Marie; Fraser, Cameron S.; Szylo, Krystina J.; Yavari, Mahsa et al. (2026-01-08). "Lymph node environment drives FSP1 targetability in metastasizing melanoma" (in en). Nature 649 (8096): 477–486. doi:10.1038/s41586-025-09709-1. ISSN 0028-0836. PMID 41193799. PMC 12779575. https://www.nature.com/articles/s41586-025-09709-1. 
  15. ↑ Nakamura, Toshitaka; Hipp, Clara; Santos Dias Mourão, André; Borggräfe, Jan; Aldrovandi, Maceler; Henkelmann, Bernhard; Wanninger, Jonas; Mishima, Eikan et al. (July 2023). "Phase separation of FSP1 promotes ferroptosis" (in en). Nature 619 (7969): 371–377. doi:10.1038/s41586-023-06255-6. ISSN 1476-4687. PMID 37380771. Bibcode: 2023Natur.619..371N. 
  16. ↑ Nakamura, Toshitaka; Hipp, Clara; Santos Dias Mourão, André; Borggräfe, Jan; Aldrovandi, Maceler; Henkelmann, Bernhard; Wanninger, Jonas; Mishima, Eikan et al. (2023-07-13). "Phase separation of FSP1 promotes ferroptosis" (in en). Nature 619 (7969): 371–377. doi:10.1038/s41586-023-06255-6. ISSN 0028-0836. PMID 37380771. PMC 10338336. https://www.nature.com/articles/s41586-023-06255-6. 
  17. ↑ Hendricks, Joseph M.; Doubravsky, Cody E.; Wehri, Eddie; Li, Zhipeng; Roberts, Melissa A.; Deol, Kirandeep K.; Lange, Mike; Lasheras-Otero, Irene et al. (September 2023). "Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis" (in en). Cell Chemical Biology 30 (9): 1090–1103.e7. doi:10.1016/j.chembiol.2023.04.007. PMID 37178691. PMC 10524360. https://linkinghub.elsevier.com/retrieve/pii/S2451945623001149. 
  18. ↑ Zhang, Sitao; Megarioti, Amalia H.; Hendricks, Joseph M.; Zhou, Junshu; Sun, Qingxiang; Jia, Da; Olzmann, James A. (2025-06-03). "Cocrystal structure reveals the mechanism of FSP1 inhibition by FSEN1" (in en). Proceedings of the National Academy of Sciences 122 (22). doi:10.1073/pnas.2505197122. ISSN 0027-8424. PMID 40440064. PMC 12146761. https://pnas.org/doi/10.1073/pnas.2505197122. 

Further reading

  • "Isolation of differentially expressed cDNAs from p53-dependent apoptotic cells: activation of the human homologue of the Drosophila peroxidasin gene". Biochemical and Biophysical Research Communications 261 (3): 864–9. August 1999. doi:10.1006/bbrc.1999.1123. PMID 10441517. Bibcode: 1999BBRC..261..864H. 
  • "Role of AIF in human coronary artery endothelial cell apoptosis". American Journal of Physiology. Heart and Circulatory Physiology 286 (1): H354-8. January 2004. doi:10.1152/ajpheart.00579.2003. PMID 14684364. 
  • "AMID is a p53-inducible gene downregulated in tumors". Oncogene 23 (40): 6815–9. September 2004. doi:10.1038/sj.onc.1207909. PMID 15273740. 
  • "Bioinformatic and image analyses of the cellular localization of the apoptotic proteins endonuclease G, AIF, and AMID during apoptosis in human cells". Apoptosis 12 (7): 1155–71. July 2007. doi:10.1007/s10495-007-0061-0. PMID 17347867. 
  • "DNA binding suppresses human AIF-M2 activity and provides a connection between redox chemistry, reactive oxygen species, and apoptosis". The Journal of Biological Chemistry 282 (41): 30331–40. October 2007. doi:10.1074/jbc.M703713200. PMID 17711848. 



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