AIFM2

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 and Marcus Conrad's group at the Helmholtz Institute 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. FSP1 also may act through the reduction of other molecules, such as vitamin E and vitamin K.

AIFM2 can be found only both in prokaryotes and eukaryotes.{{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 }}{{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 }} Sequence analysis reveals that the AIFM2 gene promoter contains a consensus transcription initiator sequence instead of a TATA box. 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.{{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}} 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. 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. It assembles stoichiometrically and noncovalently with 6-hydroxy-FAD.

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

This protein is a flavoprotein that functions as an NAD(P)H-dependent oxidoreductase and induces caspase- and p53-independent apoptosis. The exact mechanisms remain unknown, but AIFM2 is found to localize to the cytosol and the OMM. Thus, it may carry out this function by disrupting mitochondrial morphology and releasing proapoptotic factors. Also, under conditions of stress which activate p53-mediated apoptosis, such as hypoxia, AIMF2 may stabilize p53 by inhibiting its degradation and accelerate the apoptotic process. Under normal conditions (i.e., undetectable p53 expression), the AIFM2 gene is highly expressed in the heart, followed by liver and skeletal muscle, with low levels detected in the placenta, lung, kidney, and pancreas and the lowest in the brain. However, in organs such as the heart, there may be additional regulatory mechanisms to suppress its proapoptotic function. For instance, AIFM2 may be able to directly bind nuclear DNA and effect chromatin condensation, as with AIF. Furthermore, AIMF2 expressed at low levels may function as an oxidoreductase involved in metabolism. Hence, under normal cellular conditions, AIFM2 may promote cell survival rather than death by metabolic processes such as generating reactive oxygen species (ROS) to maintain survival signaling.

AIFM2 has been implicated in tumorigenesis as a p53-inducible gene. AIFM2 mRNA levels are observed to be downregulated in many human cancer tissues, though a previous study reported that AIFM2 mRNA transcripts were only detected in colon cancer and B-cell lymphoma cell lines. Furthermore, its DNA-binding ability contributes to its involvement in the apoptosis-inducing response to viral and bacterial infections, possibly through its role in ROS regulation.

Inhibitors{{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 }} of FSP1 have been identified to induce ferroptosis. icFSP1 has been shown to cause dissociation of FSP1 from the membrane and phase separation of FSP1 into droplets.

The phylogenetic studies indicates that the divergence of the AIFM1 and other AIFs occurred before the divergence of eukaryotes.

AIFM2 is shown to interact with p53.

AIFM2 is not inhibited by Bcl-2.

AIFM2 can also bind the following coenzymes:

• 6-hydroxy-FAD,
• Flavin adenine dinucleotide (FAD),
• NADPH/NADP+,
• NADH/NAD+, and
• pyridine nucleotide coenzyme.

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• {{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 }}
• {{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}}

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• {{UCSC gene info|AIFM2}}
• {{UCSC gene info|PRG3}}

Category:Proteins