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Protein AIFM1 PDB 1gv4.png
Available structures
PDBOrtholog search: PDBe RCSB
AliasesAIFM1, AIF, CMT2D, CMTX4, COWCK, COXPD6, NADMR, NAMSD, PDCD8, DFNX5, apoptosis inducing factor, mitochondria associated 1, apoptosis inducing factor mitochondria associated 1, AUNX1
External IDsOMIM: 300169 MGI: 1349419 HomoloGene: 3100 GeneCards: AIFM1
Gene location (Human)
X chromosome (human)
Chr.X chromosome (human)[1]
X chromosome (human)
Genomic location for AIFM1
Genomic location for AIFM1
BandXq26.1Start130,129,362 bp[1]
End130,165,887 bp[1]
RNA expression pattern
PBB GE AIFM1 205512 s at fs.png
More reference expression data
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr X: 130.13 – 130.17 MbChr X: 48.47 – 48.51 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Apoptosis-inducing factor 1, mitochondrial is a protein that in humans is encoded by the AIFM1 gene on the X chromosome.[5][6] This protein localizes to the mitochondria, as well as the nucleus, where it carries out nuclear fragmentation as part of caspase-independent apoptosis.[7]


AIFM1 is expressed as a 613-residue precursor protein that containing a mitochondrial targeting sequence (MTS) at its N-terminal and two nuclear leading sequences (NLS). Once imported into the mitochondria, the first 54 residues of the N-terminal are cleaved to produce the mature protein, which inserts into the inner mitochondrial membrane. The mature protein incorporates the FAD cofactor and folds into three structural domains: the FAD-binding domain, the NAD-binding domain, and the C-terminal. While the C-terminal is responsible for the proapoptotic activity of AIFM1, the FAD-binding and NAD-binding domains share the classical Rossmann topology with other flavoproteins and the NAD(P)H dependent reductase activity.[7]

Three alternative transcripts encoding different isoforms have been identified for this gene.[6] Two alternatively spliced mRNA isoforms correspond to the inclusion/exclusion of the C-terminal and the reductase domains.[7] A pseudogene that is thought to be related to this gene has been identified on chromosome 10.[6]


This gene encodes a flavoprotein essential for nuclear disassembly in apoptotic cells that is found in the mitochondrial intermembrane space in healthy cells. Induction of apoptosis results in the cleavage of this protein at residue 102 by calpains and/or cathepsins into a soluble and proapoptogenic form that translocates to the nucleus, where it effects chromosome condensation and fragmentation.[6][7] In addition, this gene product induces mitochondria to release the apoptogenic proteins cytochrome c and caspase-9.[6] AIFM1 also contributes reductase activity in redox metabolism.[7]

Clinical significance[edit]

Mutations in the AIFM1 gene are correlated with Charcot-Marie-Tooth disease (Cowchock syndrome).[7][8] At a cellular level, AIFM1 mutations result in deficiencies in oxidative phosphorylation, leading to severe mitochondrial encephalomyopathy.[6] Clinical manifestations of this mutation are characterized by muscular atrophy, neuropathy, ataxia, psychomotor regression, hearing loss and seizures.[9]


AIFM1 has been shown to interact with HSPA1A.[10][11]


Phylogenetic analysis indicates that the divergence of the AIFM1 and other human AIFs (AIFM2a and AIFM3) sequences occurred before the divergence of eukaryotes. This conclusion is supported by domain architecture of these proteins. Both eukaryotic and eubacterial AIFM1 proteins contain additional domain AIF_C.[12]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000156709 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000036932 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (February 1999). "Molecular characterization of mitochondrial apoptosis-inducing factor". Nature. 397 (6718): 441–6. doi:10.1038/17135. PMID 9989411.
  6. ^ a b c d e f "Entrez Gene: AIFM1 apoptosis-inducing factor, mitochondrion-associated, 1".
  7. ^ a b c d e f Ferreira P, Villanueva R, Martínez-Júlvez M, Herguedas B, Marcuello C, Fernandez-Silva P, Cabon L, Hermoso JA, Lostao A, Susin SA, Medina M (July 2014). "Structural insights into the coenzyme mediated monomer-dimer transition of the pro-apoptotic apoptosis inducing factor". Biochemistry. 53 (25): 4204–15. doi:10.1021/bi500343r. PMID 24914854.
  8. ^ Rinaldi C, Grunseich C, Sevrioukova IF, Schindler A, Horkayne-Szakaly I, Lamperti C, Landouré G, Kennerson ML, Burnett BG, Bönnemann C, Biesecker LG, Ghezzi D, Zeviani M, Fischbeck KH (December 2012). "Cowchock syndrome is associated with a mutation in apoptosis-inducing factor". American Journal of Human Genetics. 91 (6): 1095–102. doi:10.1016/j.ajhg.2012.10.008. PMC 3516602. PMID 23217327.
  9. ^ Kettwig M, Schubach M, Zimmermann FA, Klinge L, Mayr JA, Biskup S, Sperl W, Gärtner J, Huppke P (March 2015). "From ventriculomegaly to severe muscular atrophy: expansion of the clinical spectrum related to mutations in AIFM1". Mitochondrion. 21: 12–8. doi:10.1016/j.mito.2015.01.001. PMID 25583628.
  10. ^ Ruchalski K, Mao H, Singh SK, Wang Y, Mosser DD, Li F, Schwartz JH, Borkan SC (December 2003). "HSP72 inhibits apoptosis-inducing factor release in ATP-depleted renal epithelial cells". American Journal of Physiology. Cell Physiology. 285 (6): C1483–93. doi:10.1152/ajpcell.00049.2003. PMID 12930708.
  11. ^ Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jäättelä M, Penninger JM, Garrido C, Kroemer G (September 2001). "Heat-shock protein 70 antagonizes apoptosis-inducing factor". Nature Cell Biology. 3 (9): 839–43. doi:10.1038/ncb0901-839. PMID 11533664.
  12. ^ Klim J, Gładki A, Kucharczyk R, Zielenkiewicz U, Kaczanowski S (May 2018). "Ancestral State Reconstruction of the Apoptosis Machinery in the Common Ancestor of Eukaryotes". G3. 8 (6): 2121–2134. doi:10.1534/g3.118.200295. PMC 5982838. PMID 29703784.

Further reading[edit]

External links[edit]