Apoptosis-inducing factor 1, mitochondrial is a protein that in humans is encoded by the AIFM1gene on the X chromosome.[1][2] This protein localizes to the mitochondria, as well as the nucleus, where it carries out nuclear fragmentation as part of caspase-independent apoptosis.[3]
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 FADcofactor 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.[3]
Three alternative transcripts encoding different isoforms have been identified for this gene.[2] Two alternatively spliced mRNA isoforms correspond to the inclusion/exclusion of the C-terminal and the reductase domains.[3] A pseudogene that is thought to be related to this gene has been identified on chromosome 10.[2]
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.[2][3] In addition, this gene product induces mitochondria to release the apoptogenic proteins cytochrome c and caspase-9.[2] AIFM1 also contributes reductase activity in redox metabolism.[3]
↑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 (Feb 1999). "Molecular characterization of mitochondrial apoptosis-inducing factor". Nature. 397 (6718): 441–6. doi:10.1038/17135. PMID9989411.
↑ 3.03.13.23.33.43.5Ferreira P, Villanueva R, Martínez-Júlvez M, Herguedas B, Marcuello C, Fernandez-Silva P, Cabon L, Hermoso JA, Lostao A, Susin SA, Medina M (Jul 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. PMID24914854.
↑Kettwig M, Schubach M, Zimmermann FA, Klinge L, Mayr JA, Biskup S, Sperl W, Gärtner J, Huppke P (2015). "From ventriculomegaly to severe muscular atrophy: Expansion of the clinical spectrum related to mutations in AIFM1". Mitochondrion. 21C: 12–18. doi:10.1016/j.mito.2015.01.001. PMID25583628.
↑Ruchalski K, Mao H, Singh SK, Wang Y, Mosser DD, Li F, Schwartz JH, Borkan SC (Dec 2003). "HSP72 inhibits apoptosis-inducing factor release in ATP-depleted renal epithelial cells". Am. J. Physiol., Cell Physiol. 285 (6): C1483–93. doi:10.1152/ajpcell.00049.2003. PMID12930708.
↑Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jäättelä M, Penninger JM, Garrido C, Kroemer G (Sep 2001). "Heat-shock protein 70 antagonizes apoptosis-inducing factor". Nat. Cell Biol. 3 (9): 839–43. doi:10.1038/ncb0901-839. PMID11533664.
Further reading
Daugas E, Nochy D, Ravagnan L, Loeffler M, Susin SA, Zamzami N, Kroemer G (2000). "Apoptosis-inducing factor (AIF): a ubiquitous mitochondrial oxidoreductase involved in apoptosis". FEBS Lett. 476 (3): 118–23. doi:10.1016/S0014-5793(00)01731-2. PMID10913597.
Ferri KF, Jacotot E, Blanco J, Esté JA, Kroemer G (2001). "Mitochondrial control of cell death induced by HIV-1-encoded proteins". Ann. N. Y. Acad. Sci. 926: 149–64. doi:10.1111/j.1749-6632.2000.tb05609.x. PMID11193032.
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. PMID12022952.
Castedo M, Perfettini JL, Andreau K, Roumier T, Piacentini M, Kroemer G (2004). "Mitochondrial apoptosis induced by the HIV-1 envelope". Ann. N. Y. Acad. Sci. 1010: 19–28. doi:10.1196/annals.1299.004. PMID15033690.
Moon HS, Yang JS (2006). "Role of HIV Vpr as a regulator of apoptosis and an effector on bystander cells". Mol. Cells. 21 (1): 7–20. PMID16511342.
Daugas E, Susin SA, Zamzami N, Ferri KF, Irinopoulou T, Larochette N, Prévost MC, Leber B, Andrews D, Penninger J, Kroemer G (2000). "Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis". FASEB J. 14 (5): 729–39. PMID10744629.
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 (2002). "Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death". Nature. 410 (6828): 549–54. doi:10.1038/35069004. PMID11279485.
Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jäättelä M, Penninger JM, Garrido C, Kroemer G (2001). "Heat-shock protein 70 antagonizes apoptosis-inducing factor". Nat. Cell Biol. 3 (9): 839–43. doi:10.1038/ncb0901-839. PMID11533664.
Ye H, Cande C, Stephanou NC, Jiang S, Gurbuxani S, Larochette N, Daugas E, Garrido C, Kroemer G, Wu H (2002). "DNA binding is required for the apoptogenic action of apoptosis inducing factor". Nat. Struct. Biol. 9 (9): 680–4. doi:10.1038/nsb836. PMID12198487.
Roumier T, Vieira HL, Castedo M, Ferri KF, Boya P, Andreau K, Druillennec S, Joza N, Penninger JM, Roques B, Kroemer G (2003). "The C-terminal moiety of HIV-1 Vpr induces cell death via a caspase-independent mitochondrial pathway". Cell Death Differ. 9 (11): 1212–9. doi:10.1038/sj.cdd.4401089. PMID12404120.
