AIFM2

AIFM2
Identifiers
Aliases	AIFM2, AMID, PRG3, apoptosis inducing factor, mitochondria associated 2, apoptosis inducing factor mitochondria associated 2, FSP1
External IDs	OMIM: 605159; MGI: 1918611; HomoloGene: 6862; GeneCards: AIFM2; OMA:AIFM2 - orthologs
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10q22.1 Start 70,098,223 bp[1] End 70,132,934 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10|10 B4 Start 61,551,042 bp[2] End 61,575,039 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in adipose tissue subcutaneous adipose tissue abdominal fat mucosa of transverse colon apex of heart left ventricle right lobe of thyroid gland left coronary artery left lobe of thyroid gland right lobe of liver Top expressed in brown adipose tissue white adipose tissue adrenal gland subcutaneous adipose tissue intercostal muscle adrenal medulla mammary gland lumbar subsegment of spinal cord urinary bladder esophagus More reference expression data BioGPS n/a
Gene ontology Molecular function electron-transferring-flavoprotein dehydrogenase activity DNA binding oxidoreductase activity flavin adenine dinucleotide binding Cellular component cytoplasm integral component of membrane cytosol lipid droplet membrane mitochondrion mitochondrial outer membrane extracellular space Biological process apoptotic process apoptotic mitochondrial changes positive regulation of apoptotic process regulation of apoptotic process respiratory electron transport chain Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 84883 71361 Ensembl ENSG00000042286 ENSMUSG00000020085 UniProt Q9BRQ8 Q8BUE4 RefSeq (mRNA) NM_032797 NM_001198696 NM_001039194 NM_001284300 NM_153779 NM_178058 RefSeq (protein) NP_001185625 NP_116186 NP_001034283 NP_001271229 NP_722474 NP_835159 Location (UCSC) Chr 10: 70.1 – 70.13 Mb Chr 10: 61.55 – 61.58 Mb PubMed search [3] [4]
Wikidata
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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.^{[5][6][7][8][9][10]}

This gene encodes a flavoprotein oxidoreductase that reduces coenzyme Q10, vitamin E, and vitamin K.

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 ^[10] and Marcus Conrad's group at the Helmholtz Institute ^[9] 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.^[9][10] 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.^{[6][7][11][12]} Sequence analysis reveals that the AIFM2 gene promoter contains a consensus transcription initiator sequence instead of a TATA box.^[12] 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.^{[6][5][7][12][13]} 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.^[6] 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.^[7][5] It assembles stoichiometrically and noncovalently with 6-hydroxy-FAD.^[7]

The AIFM2 gene contains a putative p53-binding element in intron 5, suggesting that its gene expression can be activated by p53.^[5][7][12]

This protein is a flavoprotein that functions as an NAD(P)H-dependent oxidoreductase and induces caspase- and p53-independent apoptosis.^[6][5][7] 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.^[6] 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.^[5] For instance, AIFM2 may be able to directly bind nuclear DNA and effect chromatin condensation, as with AIF.^[7] Furthermore, AIMF2 expressed at low levels may function as an oxidoreductase involved in metabolism.^[5] 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.^[13]

AIFM2 has been implicated in tumorigenesis as a p53-inducible gene.^[12] 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.^[6][7] 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.^[12]

Inhibitors^[9][14] 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.^[11]

AIFM2 is shown to interact with p53.^[5]

AIFM2 is not inhibited by Bcl-2.^[5]

AIFM2 can also bind the following coenzymes:

• 6-hydroxy-FAD,^[7]
• Flavin adenine dinucleotide (FAD),^[7]
• NADPH/NADP+,^[7]
• NADH/NAD+,^[7] and
• pyridine nucleotide coenzyme.^[7]

• Human AIFM2 genome location and AIFM2 gene details page in the UCSC Genome Browser.
• Human PRG3 genome location and PRG3 gene details page in the UCSC Genome Browser.