Apoptosis-inducing factor 1, mitochondrial is a protein that in humans is encoded by the AIFM1 gene on the X chromosome. This protein localizes to the mitochondria, as well as the nucleus, where it carries out nuclear fragmentation as part of caspase-independent apoptosis.
Structure
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.
Three alternative transcripts encoding different isoforms have been identified for this gene. Two alternatively spliced mRNA isoforms correspond to the inclusion/exclusion of the C-terminal and the reductase domains. A pseudogene that is thought to be related to this gene has been identified on chromosome 10.
Function
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. In addition, this gene product induces mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. AIFM1 also contributes reductase activity in redox metabolism.
Clinical significance
Mutations in the AIFM1 gene are correlated with Charcot-Marie-Tooth disease (Cowchock syndrome). At a cellular level, AIFM1 mutations result in deficiencies in oxidative phosphorylation, leading to severe mitochondrial encephalomyopathy. Clinical manifestations of this mutation are characterized by muscular atrophy, neuropathy, ataxia, psychomotor regression, hearing loss and seizures.
Interactions
AIFM1 has been shown to interact with HSPA1A.
Evolution
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.
Further reading
- Daugas E, Nochy D, Ravagnan L, Loeffler M, Susin SA, Zamzami N, Kroemer G (July 2000). "Apoptosis-inducing factor (AIF): a ubiquitous mitochondrial oxidoreductase involved in apoptosis". FEBS Letters. 476 (3): 118–23. doi:10.1016/S0014-5793(00)01731-2. PMID 10913597. S2CID 2156881.
- Ferri KF, Jacotot E, Blanco J, Esté JA, Kroemer G (2001). "Mitochondrial control of cell death induced by HIV-1-encoded proteins". Annals of the New York Academy of Sciences. 926: 149–64. doi:10.1111/j.1749-6632.2000.tb05609.x. PMID 11193032. S2CID 21997163.
- Candé C, Cohen I, Daugas E, Ravagnan L, Larochette N, Zamzami N, Kroemer G (2002). "Apoptosis-inducing factor (AIF): a novel caspase-independent death effector released from mitochondria". Biochimie. 84 (2–3): 215–22. doi:10.1016/S0300-9084(02)01374-3. PMID 12022952.
- Castedo M, Perfettini JL, Andreau K, Roumier T, Piacentini M, Kroemer G (December 2003). "Mitochondrial apoptosis induced by the HIV-1 envelope". Annals of the New York Academy of Sciences. 1010 (1): 19–28. Bibcode:2003NYASA1010...19C. doi:10.1196/annals.1299.004. PMID 15033690. S2CID 37073602.
- Moon HS, Yang JS (February 2006). "Role of HIV Vpr as a regulator of apoptosis and an effector on bystander cells". Molecules and Cells. 21 (1): 7–20. PMID 16511342.
- Glass L (October 1975). "Classification of biological networks by their qualitative dynamics". Journal of Theoretical Biology. 54 (1): 85–107. Bibcode:1975JThBi..54...85G. doi:10.1016/S0022-5193(75)80056-7. PMID 1202295.
- Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (April 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
- Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (April 1997). "Large-scale concatenation cDNA sequencing". Genome Research. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
- Susin SA, Zamzami N, Castedo M, Daugas E, Wang HG, Geley S, Fassy F, Reed JC, Kroemer G (July 1997). "The central executioner of apoptosis: multiple connections between protease activation and mitochondria in Fas/APO-1/CD95- and ceramide-induced apoptosis". The Journal of Experimental Medicine. 186 (1): 25–37. doi:10.1084/jem.186.1.25. PMC 2198951. PMID 9206994.
- Susin SA, Lorenzo HK, Zamzami N, Marzo I, Brenner C, Larochette N, Prévost MC, Alzari PM, Kroemer G (January 1999). "Mitochondrial release of caspase-2 and -9 during the apoptotic process". The Journal of Experimental Medicine. 189 (2): 381–94. doi:10.1084/jem.189.2.381. PMC 2192979. PMID 9892620.
- Daugas E, Susin SA, Zamzami N, Ferri KF, Irinopoulou T, Larochette N, Prévost MC, Leber B, Andrews D, Penninger J, Kroemer G (April 2000). "Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis". FASEB Journal. 14 (5): 729–39. doi:10.1096/fasebj.14.5.729. PMID 10744629. S2CID 7289409.
- 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, Zúñiga-Pflücker JC, Kroemer G, Penninger JM (March 2001). "Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death". Nature. 410 (6828): 549–54. Bibcode:2001Natur.410..549J. doi:10.1038/35069004. PMID 11279485. S2CID 4387964.
- 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. S2CID 21164493.
- Ye H, Cande C, Stephanou NC, Jiang S, Gurbuxani S, Larochette N, Daugas E, Garrido C, Kroemer G, Wu H (September 2002). "DNA binding is required for the apoptogenic action of apoptosis inducing factor". Nature Structural Biology. 9 (9): 680–4. doi:10.1038/nsb836. PMID 12198487. S2CID 7819466.
- Roumier T, Vieira HL, Castedo M, Ferri KF, Boya P, Andreau K, Druillennec S, Joza N, Penninger JM, Roques B, Kroemer G (November 2002). "The C-terminal moiety of HIV-1 Vpr induces cell death via a caspase-independent mitochondrial pathway". Cell Death and Differentiation. 9 (11): 1212–9. doi:10.1038/sj.cdd.4401089. PMID 12404120.
External links
- AIFM1 on the Atlas of Genetics and Oncology
- Human AIFM1 genome location and AIFM1 gene details page in the UCSC Genome Browser.
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