AIFM1 explained

Apoptosis-inducing factor 1, mitochondrial is a protein that in humans is encoded by the AIFM1 gene 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]

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.^[3]

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.^[3] 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 affects chromosome condensation and fragmentation.^[3] 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.^[3]

Clinical significance

Mutations in the AIFM1 gene are correlated with Charcot-Marie-Tooth disease (Cowchock syndrome).^{[3] [4]} 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.^[5]

Interactions

AIFM1 has been shown to interact with HSPA1A.^{[6] [7]}

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.^[8]

References

Further reading

• Daugas E, Nochy D, Ravagnan L, Loeffler M, Susin SA, Zamzami N, Kroemer G . Apoptosis-inducing factor (AIF): a ubiquitous mitochondrial oxidoreductase involved in apoptosis . FEBS Letters . 476 . 3 . 118–23 . July 2000 . 10913597 . 10.1016/S0014-5793(00)01731-2 . 2156881 .
• Ferri KF, Jacotot E, Blanco J, Esté JA, Kroemer G . Mitochondrial control of cell death induced by HIV-1-encoded proteins . Annals of the New York Academy of Sciences . 926 . 149–64 . 2001 . 11193032 . 10.1111/j.1749-6632.2000.tb05609.x . 21997163 .
• Candé C, Cohen I, Daugas E, Ravagnan L, Larochette N, Zamzami N, Kroemer G . Apoptosis-inducing factor (AIF): a novel caspase-independent death effector released from mitochondria . Biochimie . 84 . 2–3 . 215–22 . 2002 . 12022952 . 10.1016/S0300-9084(02)01374-3 .
• Castedo M, Perfettini JL, Andreau K, Roumier T, Piacentini M, Kroemer G . Mitochondrial apoptosis induced by the HIV-1 envelope . Annals of the New York Academy of Sciences . 1010 . 1. 19–28 . December 2003 . 15033690 . 10.1196/annals.1299.004 . 2003NYASA1010...19C . 37073602 .
• Moon HS, Yang JS . Role of HIV Vpr as a regulator of apoptosis and an effector on bystander cells . Molecules and Cells . 21 . 1 . 7–20 . February 2006 . 10.1016/s1016-8478(23)12897-4 . 16511342 . free .
• Glass L . Classification of biological networks by their qualitative dynamics . Journal of Theoretical Biology . 54 . 1 . 85–107 . October 1975 . 1202295 . 10.1016/S0022-5193(75)80056-7 . 1975JThBi..54...85G .
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA . A "double adaptor" method for improved shotgun library construction . Analytical Biochemistry . 236 . 1 . 107–13 . April 1996 . 8619474 . 10.1006/abio.1996.0138 .
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA . Large-scale concatenation cDNA sequencing . Genome Research . 7 . 4 . 353–8 . April 1997 . 9110174 . 139146 . 10.1101/gr.7.4.353 .
• Susin SA, Zamzami N, Castedo M, Daugas E, Wang HG, Geley S, Fassy F, Reed JC, Kroemer G . 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 . July 1997 . 9206994 . 2198951 . 10.1084/jem.186.1.25 .
• Susin SA, Lorenzo HK, Zamzami N, Marzo I, Brenner C, Larochette N, Prévost MC, Alzari PM, Kroemer G . Mitochondrial release of caspase-2 and -9 during the apoptotic process . The Journal of Experimental Medicine . 189 . 2 . 381–94 . January 1999 . 9892620 . 2192979 . 10.1084/jem.189.2.381 .
• Daugas E, Susin SA, Zamzami N, Ferri KF, Irinopoulou T, Larochette N, Prévost MC, Leber B, Andrews D, Penninger J, Kroemer G . Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis . FASEB Journal . 14 . 5 . 729–39 . April 2000 . 10744629 . 10.1096/fasebj.14.5.729. free . 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 . Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death . Nature . 410 . 6828 . 549–54 . March 2001 . 11279485 . 10.1038/35069004 . 2001Natur.410..549J . 4387964 .
• Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jäättelä M, Penninger JM, Garrido C, Kroemer G . Heat-shock protein 70 antagonizes apoptosis-inducing factor . Nature Cell Biology . 3 . 9 . 839–43 . September 2001 . 11533664 . 10.1038/ncb0901-839 . 21164493 .
• Ye H, Cande C, Stephanou NC, Jiang S, Gurbuxani S, Larochette N, Daugas E, Garrido C, Kroemer G, Wu H . DNA binding is required for the apoptogenic action of apoptosis inducing factor . Nature Structural Biology . 9 . 9 . 680–4 . September 2002 . 12198487 . 10.1038/nsb836 . 7819466 .
• Roumier T, Vieira HL, Castedo M, Ferri KF, Boya P, Andreau K, Druillennec S, Joza N, Penninger JM, Roques B, Kroemer G . 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 . November 2002 . 12404120 . 10.1038/sj.cdd.4401089 . free .

External links

• AIFM1 on the Atlas of Genetics and Oncology

Notes and References

1. 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 . Molecular characterization of mitochondrial apoptosis-inducing factor . Nature . 397 . 6718 . 441–6 . February 1999 . 9989411 . 10.1038/17135 . 1999Natur.397..441S . 204991081 .
2. Web site: Entrez Gene: AIFM1 apoptosis-inducing factor, mitochondrion-associated, 1.
3. Ferreira P, Villanueva R, Martínez-Júlvez M, Herguedas B, Marcuello C, Fernandez-Silva P, Cabon L, Hermoso JA, Lostao A, Susin SA, Medina M . Structural insights into the coenzyme mediated monomer-dimer transition of the pro-apoptotic apoptosis inducing factor . Biochemistry . 53 . 25 . 4204–15 . July 2014 . 24914854 . 10.1021/bi500343r .
4. 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 . Cowchock syndrome is associated with a mutation in apoptosis-inducing factor . American Journal of Human Genetics . 91 . 6 . 1095–102 . December 2012 . 23217327 . 3516602 . 10.1016/j.ajhg.2012.10.008 .
5. Kettwig M, Schubach M, Zimmermann FA, Klinge L, Mayr JA, Biskup S, Sperl W, Gärtner J, Huppke P . From ventriculomegaly to severe muscular atrophy: expansion of the clinical spectrum related to mutations in AIFM1 . Mitochondrion . 21 . 12–8 . March 2015 . 25583628 . 10.1016/j.mito.2015.01.001 .
6. Ruchalski K, Mao H, Singh SK, Wang Y, Mosser DD, Li F, Schwartz JH, Borkan SC . HSP72 inhibits apoptosis-inducing factor release in ATP-depleted renal epithelial cells . American Journal of Physiology. Cell Physiology . 285 . 6 . C1483–93 . December 2003 . 12930708 . 10.1152/ajpcell.00049.2003 .
7. Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jäättelä M, Penninger JM, Garrido C, Kroemer G . Heat-shock protein 70 antagonizes apoptosis-inducing factor . Nature Cell Biology . 3 . 9 . 839–43 . September 2001 . 11533664 . 10.1038/ncb0901-839 . 21164493 .
8. Klim J, Gładki A, Kucharczyk R, Zielenkiewicz U, Kaczanowski S . Ancestral State Reconstruction of the Apoptosis Machinery in the Common Ancestor of Eukaryotes . G3 . 8 . 6 . 2121–2134 . May 2018 . 29703784 . 5982838 . 10.1534/g3.118.200295 .