AIF (Homo sapiens)

Description [+]

Synonyms: AIF, AIF, AIFM1
Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Mammalia;Primates;Hominidae; Homo sapiens
Short gene description: Apoptosis-inducing factor 1, mitochondrial Precursor (EC 1.-.-.-)(Programmed cell death protein 8)
Family: Other
Process: cell death (other),
Pathways: undefined,
Criteria: manually curated
Curator comment: The role of this protein during cell death requires further clarification
Mouse ortholog(s): Aifm1
WIKI: AIF-H_sapiens

References [+]

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
Mitochondria play a key part in the regulation of apoptosis (cell death). Their intermembrane space contains several proteins that are liberated through the outer membrane in order to participate in the degradation phase of apoptosis. Here we report the identification and cloning of an apoptosis-inducing factor, AIF, which is sufficient to induce apoptosis of isolated nuclei. AIF is a flavoprotein of relative molecular mass 57,000 which shares homology with the bacterial oxidoreductases; it is normally confined to mitochondria but translocates to the nucleus when apoptosis is induced. Recombinant AIF causes chromatin condensation in isolated nuclei and large-scale fragmentation of DNA. It induces purified mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Microinjection of AIF into the cytoplasm of intact cells induces condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of these effects is prevented by the wide-ranging caspase inhibitor known as Z-VAD.fmk. Overexpression of Bcl-2, which controls the opening of mitochondrial permeability transition pores, prevents the release of AIF from the mitochondrion but does not affect its apoptogenic activity. These results indicate that AIF is a mitochondrial effector of apoptotic cell death. Nature. 1999 Feb 4;397(6718):441-6.

AIF deficiency compromises oxidative phosphorylation.
Vahsen N, Cande C, Briere JJ, Benit P, Joza N, Larochette N, Mastroberardino PG, Pequignot MO, Casares N, Lazar V, Feraud O, Debili N, Wissing S, Engelhardt S, Madeo F, Piacentini M, Penninger JM, Schagger H, Rustin P, Kroemer G
Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, after apoptosis induction, translocates to the nucleus where it participates in apoptotic chromatinolysis. Here, we show that human or mouse cells lacking AIF as a result of homologous recombination or small interfering RNA exhibit high lactate production and enhanced dependency on glycolytic ATP generation, due to severe reduction of respiratory chain complex I activity. Although AIF itself is not a part of complex I, AIF-deficient cells exhibit a reduced content of complex I and of its components, pointing to a role of AIF in the biogenesis and/or maintenance of this polyprotein complex. Harlequin mice with reduced AIF expression due to a retroviral insertion into the AIF gene also manifest a reduced oxidative phosphorylation (OXPHOS) in the retina and in the brain, correlating with reduced expression of complex I subunits, retinal degeneration, and neuronal defects. Altogether, these data point to a role of AIF in OXPHOS and emphasize the dual role of AIF in life and death. EMBO J. 2004 Nov 24;23(23):4679-89. Epub 2004 Nov 4.

References from Mouse ortholog(s):

Loss of Aif function causes cell death in the mouse embryo, but the temporal progression of patterning is normal.
Brown D, Yu BD, Joza N, Benit P, Meneses J, Firpo M, Rustin P, Penninger JM, Martin GR
Apoptosis-inducing factor (AIF) is an evolutionarily conserved, ubiquitously expressed flavoprotein with NADH oxidase activity that is normally confined to mitochondria. In mammalian cells, AIF is released from mitochondria in response to apoptotic stimuli and translocates to the nucleus where it is thought to bind DNA and contribute to chromatinolysis and cell death in a caspase-independent manner. Here we describe the consequences of inactivating Aif in the early mouse embryo. Unexpectedly, we found that both the apoptosis-dependent process of cavitation in embryoid bodies and apoptosis associated with embryonic neural tube closure occur in the absence of AIF, indicating that Aif function is not required for apoptotic cell death in early mouse embryos. By embryonic day 9 (E9), loss of Aif function causes abnormal cell death, presumably because of reduced mitochondrial respiratory chain complex I activity. Because of this cell death, Aif null embryos fail to increase significantly in size after E9. Remarkably, patterning processes continue on an essentially normal schedule, such that E10 Aif null embryos with only approximately 1/10 the normal number of cells have the same somite number as their wild-type littermates. These observations show that pattern formation in the mouse can occur independent of embryo size and cell number. Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9918-23. Epub 2006 Jun 20.

AIF deficiency compromises oxidative phosphorylation.
Vahsen N, Cande C, Briere JJ, Benit P, Joza N, Larochette N, Mastroberardino PG, Pequignot MO, Casares N, Lazar V, Feraud O, Debili N, Wissing S, Engelhardt S, Madeo F, Piacentini M, Penninger JM, Schagger H, Rustin P, Kroemer G
Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, after apoptosis induction, translocates to the nucleus where it participates in apoptotic chromatinolysis. Here, we show that human or mouse cells lacking AIF as a result of homologous recombination or small interfering RNA exhibit high lactate production and enhanced dependency on glycolytic ATP generation, due to severe reduction of respiratory chain complex I activity. Although AIF itself is not a part of complex I, AIF-deficient cells exhibit a reduced content of complex I and of its components, pointing to a role of AIF in the biogenesis and/or maintenance of this polyprotein complex. Harlequin mice with reduced AIF expression due to a retroviral insertion into the AIF gene also manifest a reduced oxidative phosphorylation (OXPHOS) in the retina and in the brain, correlating with reduced expression of complex I subunits, retinal degeneration, and neuronal defects. Altogether, these data point to a role of AIF in OXPHOS and emphasize the dual role of AIF in life and death. EMBO J. 2004 Nov 24;23(23):4679-89. Epub 2004 Nov 4.

Structure & Sequence [+]

Pfam domains: (Pfam is a large collection of protein families.)

Source	Domain Name	Start	End
PFAM A	Pyr_redox_2	133	444
PFAM A	Pyr_redox	302	399

Protein sequence [+]

Evolution [+]

Name	Relationship	Species
A_aegypti_AAEL002016-PA	orthology	Aedes
A_gambiae_AGAP008044-PA	orthology	Anopheles
NP_001007491.1	orthology	Chicken
AIFM1	orthology	Chimpanzee
C_intestinalis_ENSCINP00000012225	orthology	Ciona
IPI00712659.1	orthology	Cow
AIFM1	orthology	Dog
CG7263	orthology	Fly
AIFM1	orthology	Fugu
AIFM1	orthology	Gasterosteus
AIFM1	orthology	Gorilla
AIFM1	orthology	Horse
AIFM1	orthology	Lyzard
AIFM1	orthology	Macaca
AIFM1	orthology	Medaka
AIFM1	orthology	Monodelphis
Aifm1	orthology	Mouse
AIFM1	orthology	Orangutan
AIFM1	orthology	Ornithorhynchus
AIFM1	orthology	Rabbit
Pdcd8	orthology	Rat
AIFM1	orthology	Tetraodon
wah-1	orthology	Worm
pdcd8	orthology	Xenopus
T_guttata_ENSTGUP00000005365	orthology	Zebra finch
T_guttata_ENSTGUP00000016816	orthology	Zebra finch
pdcd8	orthology	Zebrafish
A_aegypti_AAEL011158-PA	paralogy	Aedes
G_gallus_ENSGALP00000039047	paralogy	Chicken
AIFM3	paralogy	Chicken
AIFM3	paralogy	Chimpanzee
C_intestinalis_ENSCINP00000015763	paralogy	Ciona
Q2KJ59_BOVIN	paralogy	Cow
CG4199	paralogy	Fly
CG10700	paralogy	Fly
T_rubripes_ENSTRUP00000030429	paralogy	Fugu
AIFM3	paralogy	Fugu
T_rubripes_ENSTRUP00000040612	paralogy	Fugu
G_aculeatus_ENSGACP00000027082	paralogy	Gasterosteus
G_aculeatus_ENSGACP00000011210	paralogy	Gasterosteus
AIFM3	paralogy	Gasterosteus
AIFM3	paralogy	Human
AIFM3	paralogy	Lyzard
A_carolinensis_ENSACAP00000014484	paralogy	Lyzard
AIFM3	paralogy	Macaca
O_latipes_ENSORLP00000003241	paralogy	Medaka
O_latipes_ENSORLP00000010037	paralogy	Medaka
AIFM3	paralogy	Medaka
Aifm3	paralogy	Mouse
AIFM3	paralogy	Orangutan
RGD1306028	paralogy	Rat
AIFM3	paralogy	Tetraodon
T_nigroviridis_ENSTNIP00000019217	paralogy	Tetraodon
T_nigroviridis_ENSTNIP00000021125	paralogy	Tetraodon
F20D6.11	paralogy	Worm
AIFM3	paralogy	Xenopus
T_guttata_ENSTGUP00000005877	paralogy	Zebra finch
AIFM3	paralogy	Zebra finch
LOC569177	paralogy	Zebrafish

Gene Ontology [+]

GO id	Name	Ontology type	Evidence
GO:0008152	metabolic process	biological_proccess	IEA
GO:0045454	cell redox homeostasis	biological_proccess	IEA
GO:0008630	DNA damage response, signal transduction resulting in induction of apoptosis	biological_proccess	TAS
GO:0006309	DNA fragmentation during apoptosis	biological_proccess	TAS
GO:0006915	apoptosis	biological_proccess	IEA
GO:0055114	oxidation reduction	biological_proccess	IEA
GO:0006309	DNA fragmentation during apoptosis	biological_proccess	IEA
GO:0030263	apoptotic chromosome condensation	biological_proccess	IEA
GO:0051402	neuron apoptosis	biological_proccess	IEA
GO:0016491	oxidoreductase activity	mollecular_function	IEA
GO:0050660	FAD binding	mollecular_function	IEA
GO:0003824	catalytic activity	mollecular_function	IEA
GO:0005488	binding	mollecular_function	IEA
GO:0005515	protein binding	mollecular_function	IPI
GO:0009055	electron carrier activity	mollecular_function	TAS
GO:0003677	DNA binding	mollecular_function	IEA
GO:0005737	cytoplasm	cell_component	IEA
GO:0005634	nucleus	cell_component	TAS
GO:0005739	mitochondrion	cell_component	TAS
GO:0005758	mitochondrial intermembrane space	cell_component	IEA
GO:0005634	nucleus	cell_component	IEA
GO:0005739	mitochondrion	cell_component	IEA
GO:0005792	microsome	cell_component	IEA
GO:0005625	soluble fraction	cell_component	IEA

Check GO Evidence Codes here

KEGG Pathways [+]

Curated Isoforms [+]

Transcript	Translation
OTTHUMT00000058247 *	OTTHUMP00000024007 *
OTTHUMT00000058248	OTTHUMP00000024008
OTTHUMT00000058249	OTTHUMP00000024009
OTTHUMT00000058250

Information from other databases [+]

Gene related links:

Gene info from HGNC [?] :8768
Gene related info from GeneCards [?] : AIF
Ensembl genome browser [?] : ENSG00000156709
Expression info from Arrayexpress [?] : ENSG00000156709
Protein expression from Protein Atlas: [?] ENSG00000156709
Community gene edition from Wikigenes: [?] 9131

Protein related links:

Uniprot protein info: O95831
PIR protein info: O95831
Protein interactions from IntAct: O95831

Gene and disease information from OMIM: (For a full disease description table, click here.)

OMIM gene information: 300169
OMIM disease information:

Other links

entrezgene: 9131
refseq_dna: NM_001130847
refseq_dna: NM_001130846
refseq_dna: NM_004208
refseq_dna: NM_145812
refseq_dna: NM_145813
refseq_peptide: NP_004199
refseq_peptide: NP_001124319
refseq_peptide: NP_001124318
refseq_peptide: NP_665811
refseq_peptide: NP_665812

Click on [?] for more information.