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AIFM1 (apoptosis-inducing factor, mitochondrion-associated, 1)

Written2007-10Victor J Yuste, Hans K Lorenzo, Santos A Susin
Cell Death, Senescence, Survival Research Group, Institut de Neurociencies, Universitat Autonoma de Barcelona (UAB), Edifici M, Campus de Bellaterra, 08193 Bellaterra (Cerdanyola del Valles), Spain (VJY); University of Paris XI, School of Medicine, Hospital Paul Brousse, INSERM U542, 14, av. Paul Vaillant Couturier, 94807 Villejuif, France (HKL); Apoptosis, Immune System, Institut Pasteur, URA 1961-CNRS, 25, rue du Dr. Roux, 75724 Paris Cedex 15, France (SAS)

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HGNC Alias symbAIF
HGNC Previous namePDCD8
HGNC Previous nameprogrammed cell death 8 (apoptosis-inducing factor)
 neuropathy, axonal, motor-sensory with deafness and mental retardation (Cowchock syndrome)
 apoptosis-inducing factor, mitochondrion-associated, 1
 apoptosis inducing factor, mitochondria associated 1
 auditory neuropathy, X-linked recessive 1
LocusID (NCBI) 9131
Atlas_Id 44053
Location Xq26.1  [Link to chromosome band Xq26]
Location_base_pair Starts at 130129363 and ends at 130165887 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping AIFM1.png]
Local_order Centromere (59,500 Kbp)- ARHGEF9 - (...) - RAB33A- AIFM1 - ELF4 - (...) - IL9R -telomere (154,914 Kbp).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
AIFM1 (Xq26.1)::AIFM1 (Xq26.1)GCSAML (1q44)::AIFM1 (Xq26.1)SNHG3 (1p35.3)::AIFM1 (Xq26.1)


Note AIF (Apoptosis-Inducing Factor). Total gene size 36.471 Kb with a transcribed region of 2.215 Kb which codes for 613 amino acids. To date, five isoforms from AIF gene have been described (AIF, AIFexB, AIFsh, AIFsh2, and AIFsh3).
  AIF gene structure and known isoforms. Genomic organization of AIF and resulting AIF, AIF-exB, AIFsh, AIFsh2, and AIFsh3 mRNA transcripts (schemas in the left). Translation start (ATG, in green) and stop (TGA/TAA, in red) codons are indicated, and the predicted protein product is shown at the right. Numbers in AIF designate exons (in mRNA transcripts) and amino acids (in the predicted proteins). Mitochondria localization signal (MLS), Pyridoxin-redox (Pyr-Redox), nuclear localization sequence (NLS), and C-terminal domains are indicated. I9 (in green) indicates intron 9. The inclusion of the 203-bp exon 9b (lettering in red) produces AIFsh2 and AIFsh3, which encodes 324- and 237-amino acid proteins, respectively. AIFsh2 contains the MLS and the Pyr-Redox domain, but lacks the C-terminal portion of AIF. AIFsh3 has a similar structure as AIFsh2 with the splicing of exon 2, leading to the loss of MLS. Blue lines indicate the splicing of the different isoforms.
Description 16 exons spanning 36.471 Kb.
Transcription 2,215 bp mRNA.
Pseudogene Not known.


Note 613 amino acids long protein whose structure may be divided into three domains: a FAD-binding domain (residues 128-262 and 401-480), a NADH-binding domain (residues 263-400), and a C-terminal domain (residues 481-608).
  Schematic model representing the three different AIF forms: precursor, mature, and truncated. AIF is a flavoprotein (with an oxidoreductase enzymatic activity) containing a FAD-bipartite domain (yellow, amino-acids 128-262 and 401-480), a NADH-binding motif (violet, amino-acids 263-400), and a C-terminal domain (red, amino-acids 481-608) where the proapoptotic activity of the protein resides. In addition, it has a Mitochondria Localization Sequence (MLS, in green, amino-acids 1-41) placed in its N-terminal region. Between the first-N-terminal FAD motif and the MLS, AIF possesses a potential Transmembrane Domain (TM, in green, amino-acids 67-83). This TM is flanked by two peptidase-processing positions: a Mitochondrial Processing Peptidase (MPP)-cleavage site (in blue, amino-acid 54) and a calpains- and/or cathepsins-cleavage site (in red, amino-acid 103). Hsp70 (Heat Shock Protein-70) and CypA (Cyclophilin A) bind AIF in amino-acids 150-228 and 367-369, respectively. AIF also possesses two DNA-binding sites, which are located in amino-acids 255-265 and 510-518, respectively. AIF precursor protein has 613 amino-acids. The MPP-mediated cleavage generates the mitochondrial mature AIF (amino-acids 55-613). After an apoptotic insult, calpains or cathepsins cleave AIF to produce truncated-AIF (tAIF), which is released from mitochondria to cytosol (amino-acids 104-613).
Description AIF was initially identified as a protein released from the mitochondrial intermembrane space during the apoptotic process. First studies showed that upon an apoptotic stimulus AIF translocates from mitochondria to cytosol and further to the nucleus where it triggers caspase-independent programmed cell death. AIF, expressed as a precursor of 67 kDa, is addressed to mitochondria by the two MLS placed within the N-terminal prodomain of the protein. Once in mitochondria, this precursor is processed to a mature form of 62 kDa by a first proteolytic cleavage. In this configuration, AIF is an inner-membrane-anchored protein in which the N-terminus is exposed to the mitochondrial matrix and the C-terminal portion to the mitochondrial intermembrane space. AIF is here required for maintenance or maturation of the mitochondrial respiratory chain complex I. After a cell death insult, the 62 kDa AIF-mitochondrial form is cleaved by activated calpains and/or cathepsins to yield a soluble proapoptotic protein with an apparent molecular weight of 57 kDa tAIF (truncated AIF). tAIF is released from mitochondria to cytosol and nucleus to generate two typical hallmarks of caspase-independent programmed cell death: chromatin condensation and large-scale approximatively 50 kb DNA fragmentation.
  Ribbon structure of mouse AIF in its mature form (pdb id: 1GV4). As depicted here, three domains are present in the protein. The FAD-binding domain and the NAD-binding domain (yellow) are both similar to oxidoreductase domains from members of the glutathione reductase family. In contrast, the C-terminal domain (blue) displays a particular folding with a specific insertion, which includes residues 580 to 610. This picture also includes the AIF cofactor Flavin Adenine Dinucleotide (FAD; magenta).
Expression Ubiquitously expressed.
Localisation Mitochondrion.
Function AIF has a double life/death function.
In its vital role, AIF is required to maintain and/or organize the mitochondrial respiratory complex I, and displays NADH oxidoreductase and peroxide scavenging activities. In addition to this vital function, AIF has been shown to be implicated in programmed cell death (PCD) induction in several experimental models (see bibliography section). In the two most studied AIF-dependent PCD models, AIF death activity is associated with the increase of intracellular Ca2+ (e.g., ischemia/reperfusion injury), or relates with extensive DNA-damage (e.g., treatment with alkylating agents). In the first model, increased intracellular Ca2+ levels trigger depolarization of mitochondrial membrane, subsequent loss of membrane potential, generation of reactive oxygen species (ROS), and AIF mitochondrial release. In the second model, extensive DNA damage, provoked by high doses of alkylating agents such as MNNG or MNU, triggers poly(ADP-ribose) polymerase-1 (PARP-1) over-activation and AIF release from the mitochondrial intermembrane space. This cell death pathway sequentially involves PARP-1, calpains, Bax, and AIF.
Homology AIF is a highly conserved protein ubiquitously present in all primary kingdoms, Bacteria, Archaea and Eucaryota. The aif gene is inherited from the last universal common ancestor and follows the tree topology with the primary radiation of the archaeo-eukaryotic and bacterial clades. AIF also has a highly significant homology with different families of oxidoreductases, including NADH oxydases, Ascorbate reductases, Glutathione reductases and many NADH-dependent ferredoxin reductases from Archaea and Bacteria to invertebrates and vertebrates.
Mouse, Rat homology


Note Several polymorphisms have been identified but none of them has shown any association with a disease.

Implicated in

Entity Various cancers
Note Upregulated in cancers (colorectal carcinoma, gastric carcinoma, breast carcinoma and hepatocellular carcinoma, glioblastoma).
AIF expression may play a role in tumor formation and could maintain a transformed state of colon cancer cells involving mitochondrial complex I function.
Entity Cell death
Disease AIF has been directly designed as main mediator of cell death in ischemic injuries after overproduction of reactive oxygen species. Indeed, blocking the mitochondrial release of AIF to cytosol and its further nuclear translocation provides protection against neuronal and cardiomyocites cell death. AIF-deficient harlequin mutant mouse presents a significant reduction of neuronal cell death in brain trauma and cerebral ischemia. A similar protective effect was observed in AIF siRNA-treated neurons.
Entity Degenerative disorders
Disease AIF is involved in several degenerative disorders. The elevated production of ROS generated in Amyotrophic Lateral Sclerosis, Alzheimer's, or Parkinson diseases concludes in the translocation of AIF. Likewise, AIF release triggered by calpains and cathepsins was observed on in vitro models of Epilepsy and Huntington's disease. AIF-mediated cell death is involved in the pathogenesis of different retinal affections such as retinal detachment, retinitis pigmentosa, or in models of retinal hypoxia. Moreover, an increase of AIF expression has been reported in patients affected with diabetic retinopathy.


CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells.
Artus C, Maquarre E, Moubarak RS, Delettre C, Jasmin C, Susin SA, Robert-Lézé J
Oncogene. 2006 ; 25 (42) : 5741-5751.
PMID 16636662
Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis.
Bidère N, Lorenzo HK, Carmona S, Laforge M, Harper F, Dumont C, Senik A
The Journal of biological chemistry. 2003 ; 278 (33) : 31401-31411.
PMID 12782632
AIF-mediated programmed necrosis: a highly regulated way to die.
Boujrad H, Gubkina O, Robert N, Krantic S, Susin SA
Cell cycle (Georgetown, Tex.). 2007 ; 6 (21) : 2612-2619.
PMID 17912035
AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis.
Candé C, Vahsen N, Kouranti I, Schmitt E, Daugas E, Spahr C, Luban J, Kroemer RT, Giordanetto F, Garrido C, Penninger JM, Kroemer G
Oncogene. 2004 ; 23 (8) : 1514-1521.
PMID 14716299
Dissociating the dual roles of apoptosis-inducing factor in maintaining mitochondrial structure and apoptosis.
Cheung EC, Joza N, Steenaart NA, McClellan KA, Neuspiel M, McNamara S, MacLaurin JG, Rippstein P, Park DS, Shore GC, McBride HM, Penninger JM, Slack RS
The EMBO journal. 2006 ; 25 (17) : 4061-4073.
PMID 16917506
Identification and characterization of AIFsh2, a mitochondrial apoptosis-inducing factor (AIF) isoform with NADH oxidase activity.
Delettre C, Yuste VJ, Moubarak RS, Bras M, Robert N, Susin SA
The Journal of biological chemistry. 2006 ; 281 (27) : 18507-18518.
PMID 16644725
Apoptosis-inducing factor determines the chemoresistance of non-small-cell lung carcinomas.
Gallego MA, Joseph B, Hemström TH, Tamiji S, Mortier L, Kroemer G, Formstecher P, Zhivotovsky B, Marchetti P
Oncogene. 2004 ; 23 (37) : 6282-6291.
PMID 15286713
Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor.
Gurbuxani S, Schmitt E, Cande C, Parcellier A, Hammann A, Daugas E, Kouranti I, Spahr C, Pance A, Kroemer G, Garrido C
Oncogene. 2003 ; 22 (43) : 6669-6678.
PMID 14555980
Immunohistochemical and mutational analysis of apoptosis-inducing factor (AIF) in colorectal carcinomas.
Jeong EG, Lee JW, Soung YH, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 2006 ; 114 (12) : 867-873.
PMID 17207087
Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death.
Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY, Sasaki T, Elia AJ, Cheng HY, Ravagnan L, Ferri KF, Zamzami N, Wakeham A, Hakem R, Yoshida H, Kong YY, Mak TW, Zñiga-Pflücker JC, Kroemer G, Penninger JM
Nature. 2001 ; 410 (6828) : 549-554.
PMID 11279485
The harlequin mouse mutation downregulates apoptosis-inducing factor.
Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, Bronson RT, Ackerman SL
Nature. 2002 ; 419 (6905) : 367-374.
PMID 12353028
Therapeutic potential of AIF-mediated caspase-independent programmed cell death.
Lorenzo HK, Susin SA
Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 2007 ; 10 (6) : 235-255.
PMID 18180198
The crystal structure of the mouse apoptosis-inducing factor AIF.
Maté MJ, Ortiz-Lombardía M, Boitel B, Haouz A, Tello D, Susin SA, Penninger J, Kroemer G, Alzari PM
Nature structural biology. 2002 ; 9 (6) : 442-446.
PMID 11967568
NADH oxidase activity of mitochondrial apoptosis-inducing factor.
Miramar MD, Costantini P, Ravagnan L, Saraiva LM, Haouzi D, Brothers G, Penninger JM, Peleato ML, Kroemer G, Susin SA
The Journal of biological chemistry. 2001 ; 276 (19) : 16391-16398.
PMID 11278689
Apoptosis-inducing factor: vital and lethal.
Modjtahedi N, Giordanetto F, Madeo F, Kroemer G
Trends in cell biology. 2006 ; 16 (5) : 264-272.
PMID 16621561
Sequential activation of poly(ADP-ribose) polymerase 1, calpains, and Bax is essential in apoptosis-inducing factor-mediated programmed necrosis.
Moubarak RS, Yuste VJ, Artus C, Bouharrour A, Greer PA, Menissier-de Murcia J, Susin SA
Molecular and cellular biology. 2007 ; 27 (13) : 4844-4862.
PMID 17470554
Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space.
Otera H, Ohsakaya S, Nagaura Z, Ishihara N, Mihara K
The EMBO journal. 2005 ; 24 (7) : 1375-1386.
PMID 15775970
Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria.
Polster BM, Basañez G, Etxebarria A, Hardwick JM, Nicholls DG
The Journal of biological chemistry. 2005 ; 280 (8) : 6447-6454.
PMID 15590628
Heat-shock protein 70 antagonizes apoptosis-inducing factor.
Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jäättelä M, Penninger JM, Garrido C, Kroemer G
Nature cell biology. 2001 ; 3 (9) : 839-843.
PMID 11533664
Distinct hsp70 domains mediate apoptosis-inducing factor release and nuclear accumulation.
Ruchalski K, Mao H, Li Z, Wang Z, Gillers S, Wang Y, Mosser DD, Gabai V, Schwartz JH, Borkan SC
The Journal of biological chemistry. 2006 ; 281 (12) : 7873-7880.
PMID 16407317
Regulation of AIF expression by p53.
Stambolsky P, Weisz L, Shats I, Klein Y, Goldfinger N, Oren M, Rotter V
Cell death and differentiation. 2006 ; 13 (12) : 2140-2149.
PMID 16729031
Molecular characterization of mitochondrial apoptosis-inducing factor.
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
Nature. 1999 ; 397 (6718) : 441-446.
PMID 9989411
AIF suppresses chemical stress-induced apoptosis and maintains the transformed state of tumor cells.
Urbano A, Lakshmanan U, Choo PH, Kwan JC, Ng PY, Guo K, Dhakshinamoorthy S, Porter A
The EMBO journal. 2005 ; 24 (15) : 2815-2826.
PMID 16001080
Physical interaction of apoptosis-inducing factor with DNA and RNA.
Vahsen N, Candé C, Dupaigne P, Giordanetto F, Kroemer RT, Herker E, Scholz S, Modjtahedi N, Madeo F, Le Cam E, Kroemer G
Oncogene. 2006 ; 25 (12) : 1763-1774.
PMID 16278674
DNA binding is required for the apoptogenic action of apoptosis inducing factor.
Ye H, Cande C, Stephanou NC, Jiang S, Gurbuxani S, Larochette N, Daugas E, Garrido C, Kroemer G, Wu H
Nature structural biology. 2002 ; 9 (9) : 680-684.
PMID 12198487
Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death.
Yu SW, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM, Dawson VL
Proceedings of the National Academy of Sciences of the United States of America. 2006 ; 103 (48) : 18314-18319.
PMID 17116881
Poly(ADP-ribose) polymerase-1 and apoptosis inducing factor in neurotoxicity.
Yu SW, Wang H, Dawson TM, Dawson VL
Neurobiology of disease. 2003 ; 14 (3) : 303-317.
PMID 14678748
Cysteine protease inhibition prevents mitochondrial apoptosis-inducing factor (AIF) release.
Yuste VJ, Moubarak RS, Delettre C, Bras M, Sancho P, Robert N, d'Alayer J, Susin SA
Cell death and differentiation. 2005 ; 12 (11) : 1445-1448.
PMID 15933737


This paper should be referenced as such :
Yuste, VJ ; Lorenzo, HK ; Susin, SA
AIFM1 (apoptosis-inducing factor, mitochondrion-associated, 1)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3):190-194.
Free journal version : [ pdf ]   [ DOI ]

External links

HGNC (Hugo)AIFM1   8768
Entrez_Gene (NCBI)AIFM1    apoptosis inducing factor mitochondria associated 1
AliasesAIF; AUNX1; CMT2D; CMTX4; 
GeneCards (Weizmann)AIFM1
Ensembl hg19 (Hinxton)ENSG00000156709 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000156709 [Gene_View]  ENSG00000156709 [Sequence]  chrX:130129363-130165887 [Contig_View]  AIFM1 [Vega]
ICGC DataPortalENSG00000156709
TCGA cBioPortalAIFM1
Genatlas (Paris)AIFM1
SOURCE (Princeton)AIFM1
Genetics Home Reference (NIH)AIFM1
Genomic and cartography
GoldenPath hg38 (UCSC)AIFM1  -     chrX:130129363-130165887 -  Xq26.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)AIFM1  -     Xq26.1   [Description]    (hg19-Feb_2009)
GoldenPathAIFM1 - Xq26.1 [CytoView hg19]  AIFM1 - Xq26.1 [CytoView hg38]
Genome Data Viewer NCBIAIFM1 [Mapview hg19]  
OMIM300169   300232   300614   300614   300816   310490   310490   
Gene and transcription
Genbank (Entrez)AF100928 AF131759 AI521711 AK000775 AK314446
RefSeq transcript (Entrez)NM_001130846 NM_001130847 NM_004208 NM_145812 NM_145813
Consensus coding sequences : CCDS (NCBI)AIFM1
Gene ExpressionAIFM1 [ NCBI-GEO ]   AIFM1 [ EBI - ARRAY_EXPRESS ]   AIFM1 [ SEEK ]   AIFM1 [ MEM ]
Gene Expression Viewer (FireBrowse)AIFM1 [ Firebrowse - Broad ]
GenevisibleExpression of AIFM1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9131
GTEX Portal (Tissue expression)AIFM1
Human Protein AtlasENSG00000156709-AIFM1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)AIFM1
Human Protein Atlas [tissue]ENSG00000156709-AIFM1 [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed330 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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