| *300169 | |||||||||||||||||||||||||||||||||
| APOPTOSIS-INDUCING FACTOR, MITOCHONDRION-ASSOCIATED, 1; AIFM1 | |||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||
| APOPTOSIS-INDUCING FACTOR; AIF PROGRAMMED CELL DEATH 8; PDCD8 | |||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: AIFM1 | |||||||||||||||||||||||||||||||||
| Cytogenetic location: Xq26.1 Genomic coordinates (GRCh37): X:129,263,336 - 129,299,860 (from NCBI) | |||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||||||||
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| TEXT | |||||||||||||||||||||||||||||||||
| Description | |||||||||||||||||||||||||||||||||
| The AIFM1 gene encodes a mitochondrial flavin adenine dinucleotide (FAD)-dependent oxidoreductase that plays a role in oxidative phosphorylation (OxPhos) and redox control in healthy cells. After mitochondrial outer membrane permeabilization, which is a feature of most, if not all, apoptotic pathways, AIFM1 is released from mitochondria and translocates to the nucleus, where it mediates nuclear features of apoptosis such as chromatin condensation and large-scale DNA degradation (summary by Joza et al., 2009). | |||||||||||||||||||||||||||||||||
| Cloning | |||||||||||||||||||||||||||||||||
| Susin et al. (1999) identified and cloned an apoptosis-inducing factor, AIF, that is sufficient to induce apoptosis of isolated nuclei. They cloned the mouse homolog of AIF, which has 92% amino acid identity to the human protein. The full-length proteins of both mouse and human contain 2 mitochondrial localization sequences and 2 putative nuclear localization signals. Mature mouse AIF has a molecular mass 57 kD that shares homology with the bacterial oxidoreductases, whereas the mouse precursor AIF transcript is 67 kD. AIF was normally confined to the mitochondrial intermembrane space, but translocated to the nucleus when apoptosis is induced. Recombinant AIF caused chromatin condensation and large scale fragmentation of DNA in isolated HeLa cell nuclei. It induced purified mitochondria to release the apoptogenic proteins cytochrome c (123970) and caspase-9 (602234). Microinjection of AIF into the cytoplasm of intact cells induced condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of the effects were prevented by pretreatment with a caspase inhibitor. Overexpression of BCL2 (151430), which controls the opening of mitochondrial permeability transition pores, prevented the release of AIF from the mitochondrion, but did not affect its apoptogenic activity. Susin et al. (1999) concluded that AIF is the principal mitochondrial factor causing nuclear apoptosis. They postulated that the caspases, DFF/CAD (601883), and AIF are engaged in complementary cooperative or redundant pathways that lead to nuclear apoptosis. Ghezzi et al. (2010) identified human AIF as a 62-kD mature mitochondrion-specific protein that binds FAD and attaches by an N-terminal transmembrane domain to the inner mitochondrial membrane, where is functions as an NADH oxidase. Upon apoptogenic stimuli, the 57-kD soluble AIF containing 512 amino acids is released by proteolytic cleavage and translocates from the mitochondria to the nucleus, where it binds to chromosomal DNA and induces chromatin condensation and DNA fragmentation by attracting and activating a set of endonucleases. The full-length human precursor protein is a 67-kD polypeptide and contains 613 amino acids. After mitochondrial import, cleavage of a 54-amino acid mitochondrial targeting sequence results in the 62-kD mature protein containing 559 amino acids. | |||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||
| By its inclusion within a mapped clone (GenBank Z81364), Susin et al. (1999) mapped the AIFM1 gene to chromosome Xq25-q26. | |||||||||||||||||||||||||||||||||
| Gene Function | |||||||||||||||||||||||||||||||||
| Programmed cell death is a fundamental requirement for embryogenesis, organ metamorphosis, and tissue homeostasis. In mammals, release of mitochondrial cytochrome c leads to cytosolic assembly of the apoptosome--a caspase activation complex involving APAF1 (602233) and caspase-9 that induces hallmarks of apoptosis. There are, however, mitochondrially regulated cell death pathways that are independent of APAF1/caspase-9. Like cytochrome c, AIF is localized to mitochondria and released in response to death stimuli. Joza et al. (2001) showed that genetic inactivation of AIF renders embryonic stem cells resistant to cell death after serum deprivation. Moreover, AIF is essential for programmed cell death during cavitation of embryoid bodies--the very first wave of cell death indispensable for mouse morphogenesis. AIF-dependent cell death displays structural features of apoptosis, and can be genetically uncoupled from APAF1 and caspase-9 expression. Joza et al. (2001) concluded that their data provide genetic evidence for a caspase-independent pathway of programmed cell death that controls early morphogenesis. Yu et al. (2002) demonstrated that poly(ADP-ribose) polymerase-1 (PARP1; 173870) activation is required for translocation of AIF from the mitochondria to the nucleus and that AIF is necessary for PARP1-dependent cell death. N-methyl-N-prime-nitro-N-nitrosoguanidine, hydrogen peroxide, and NMDA induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP1-dependent cytotoxicity. Yu et al. (2002) concluded that their data support a model in which PARP1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death. Andrabi et al. (2006) and Yu et al. (2006) demonstrated that the product of PARP1 activity, poly(ADP-ribose) (PAR) polymer, mediates PARP1-induced cell death. Yu et al. (2006) showed that PAR polymer induced the release of Aif from mitochondria in mouse cortical neurons and induced its translocation to nuclei. They also showed that poly(ADP-ribose) glycohydrolase (PARG; 603501) prevented Parp1-dependent Aif release. Furthermore, cells with reduced levels of Aif were resistant to PARP1-dependent cell death and PAR polymer cytotoxicity. Joza et al. (2009) provided a review of AIFM1 functional and animal model studies and discussed its role in caspase-independent cell death pathways, mitochondrial metabolism and redox control, and obesity and diabetes. | |||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||
| In 2 Italian male first-cousins, born of monozygotic twin sisters and unrelated fathers, with combined oxidative phosphorylation deficiency resulting in a severe mitochondrial encephalomyopathy (COXPD6; 300816), Ghezzi et al. (2010) identified a hemizygous deletion in the AIFM1 gene (300169.0001). Both had onset in the first year of life of psychomotor regression, muscle weakness and atrophy, lack of further development, and abnormal signals in the basal ganglia. One died at age 16 months, and the other was tetraplegic and wheelchair-bound with an inability to communicate at age 5 years. In vitro studies showed that the AIFM1 mutation resulted in destabilization of the inner mitochondrial membrane with subsequent damage to respiratory chain structure and activities. In addition, the mutation resulted in impaired control of mitochondrion-derived programmed cell death. | |||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||
| Harlequin (Hq) mutant mice have progressive degeneration of terminally differentiated cerebellar and retinal neurons. Klein et al. (2002) identified the Hq mutation as a proviral insertion in the Aif gene, causing an approximately 80% reduction in Aif expression. Mutant cerebellar granular cells were susceptible to exogenous and endogenous peroxide-mediated apoptosis, but could be rescued by Aif expression. Overexpression of Aif in wildtype granule cells further decreased peroxide-mediated cell death, suggesting that AIF serves as a free radical scavenger. In agreement, dying neurons in aged Hq mutant mice showed oxidative stress. In addition, neurons damaged by oxidative stress in both the cerebellum and retina of Hq mutant mice reentered the cell cycle before undergoing apoptosis. The results of Klein et al. (2002) provided a genetic model of oxidative stress-mediated neurodegeneration and demonstrated a direct connection between cell cycle reentry and oxidative stress in the aging central nervous system. Wang et al. (2002) reported that inactivation of the C. elegans AIF homolog WAH-1 by RNA interference delayed the normal progression of apoptosis and caused a defect in apoptotic DNA degradation. WAH-1 localized in C. elegans mitochondria and was released into the cytosol and nucleus by the BH3-domain protein EGL1 (606266) in a caspase (CED3)-dependent manner. In addition, WAH-1 associated and cooperated with the mitochondrial endonuclease CPS6-endonuclease G (600440) to promote DNA degradation and apoptosis. Thus, AIF and EndoG define a single, mitochondria-initiated apoptotic DNA degradation pathway that is conserved between C. elegans and mammals. Brown et al. (2006) found that inactivating Aif in the early mouse embryo had no effect on the apoptosis-dependent process of cavitation in embryoid bodies and apoptosis associated with embryonic neural tube closure, indicating that Aif function is not required for apoptotic cell death in early mouse embryos. By embryonic day 9, loss of Aif function caused abnormal cell death, presumably due to reduced mitochondrial respiratory chain complex-1 activity. Because of this cell death, Aif-null embryos failed to increase significantly in size after embryonic day 9. However, patterning continued on an essentially normal schedule, such that embryonic day-10 Aif-null embryos with only about 10% of the normal cell number had the same somite number as their wildtype littermates. Brown et al. (2006) concluded that pattern formation in the mouse can occur independent of embryo size and cell number. In the rd1 mouse model of retinitis pigmentosa (see 180072) and an in vitro cellular model, Sanges et al. (2006) found that both Aif and caspase-12 (CASP12; 608633) translocated to the nucleus of dying photoreceptors. Only differentiated rd1 photoreceptors underwent apoptosis, and apoptosis was never observed in amacrine, bipolar, or horizontal retinal neurons. Translocation of both apoptotic factors required increased intracellular calcium, and calpain (see CAPN1; 114220) inhibitors interfered with Aif and Casp12 activation and rd1 photoreceptor apoptosis. Knockdown of Aif or Casp12 by interfering RNA showed that Aif played a major role in this apoptotic event and that Casp12 had a reinforcing effect. | |||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||||||||||||||
| Table View | |||||||||||||||||||||||||||||||||
| .0001 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6 | |||||||||||||||||||||||||||||||||
| AIFM1, 3-BP DEL, 601AGA | |||||||||||||||||||||||||||||||||
| In 2 Italian male first-cousins, born of monozygotic twin sisters and unrelated fathers, with combined oxidative phosphorylation deficiency resulting in a severe mitochondrial encephalomyopathy (COXPD6; 300816), Ghezzi et al. (2010) identified a hemizygous 3-bp deletion (601delAGA) in the AIFM1 gene, resulting in the deletion of arg201. Both had onset in the first year of life of psychomotor regression, muscle weakness and atrophy, lack of further development, and abnormal signals in the basal ganglia. One died at age 16 months, and the other was tetraplegic and wheelchair-bound with an inability to communicate at age 5 years. In silico analysis indicated that arg201 residue is part of a hairpin that forms the FAD-binding pouch and confers conformational stability to the flavoprotein. Thus, deletion of arg201 probably perturbs the functional properties of both oxidized and reduced forms of AIF. In vitro studies showed that the lifetime of the FADH2-NAD complex formed by mutant mitochondrial AIF was shorter than that observed with wildtype. The mutant protein also had increased susceptibility to proteolytic cleavage, indicating that it is a structurally unstable variant. The mutant protein also showed higher DNA binding affinity and potential ability to cause DNA damage compared to wildtype. Approximately 75% of mutant cells versus 23% of control cells showed mitochondrial fragmentation under galactose treatment, suggesting that cells containing the mutant are more sensitive to apoptotic stimuli than control cells. Mitochondrial fragmentation was associated with impaired oxidative phosphorylation. Riboflavin treatment of cells with the mutant protein showed a recovery of the filamentous network and improvement in cell viability, which corresponded to some clinical improvement seen in 1 of the patients with the mutation. Overall, the studies showed that the AIFM1 mutation resulted in destabilization of the inner mitochondrial membrane with subsequent damage to respiratory chain structure and activities. In addition, the mutation resulted in impaired control of mitochondrion-derived programmed cell death. | |||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||
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