Disease relevance of Aifm1

• The translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus has been implicated in the mechanism of glutamate excitotoxicity in cortical neurons and has been observed in vivo following acute rodent brain injuries [1].
• Apoptosis inducing factor mediates caspase-independent 1-methyl-4-phenylpyridinium toxicity in dopaminergic cells [2].
• Apoptosis inducing factor and PARP-mediated injury in the MPTP mouse model of Parkinson's disease [3].
• 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 [4].
• Muscle-specific loss of apoptosis-inducing factor leads to mitochondrial dysfunction, skeletal muscle atrophy, and dilated cardiomyopathy [5].

High impact information on Aifm1

• Dueling activities of AIF in cell death versus survival: DNA binding and redox activity [6].
• Mutant cerebellar granule cells are susceptible to exogenous and endogenous peroxide-mediated apoptosis, but can be rescued by AIF expression [7].
• Like cytochrome c, AIF is localized to mitochondria and released in response to death stimuli [8].
• Here we show that genetic inactivation of AIF renders embryonic stem cells resistant to cell death after serum deprivation [8].
• Moreover, AIF is essential for programmed cell death during cavitation of embryoid bodies-the very first wave of cell death indispensable for mouse morphogenesis [8].

Chemical compound and disease context of Aifm1

• Taken together, genistein-induced apoptosis of p815 mastocytoma cells is at least in part mediated by proteasome, Bax, apoptosis-inducing factor, and caspase and augmented by cotreatment with a proteasome inhibitor, lactacystin [9].
• To investigate the role of AIF in the apoptotic process in vivo, we induced retinal detachment (RD) by subretinal injection of sodium hyaluronate, either in Brown Norway rats or in C3H mice [10].
• Here, we generated a chimeric immuno-AIF protein, which comprised an HER2 antibody, a Pseudomonas exotoxin translocation domain and AIFDelta1-120 [11].

Biological context of Aifm1

• Microinjection of neutralizing antibodies against AIF significantly decreased injury-induced neuronal cell death in Apaf1-deficient neurons, indicating its importance in caspase-independent apoptosis [12].
• The Bcl-2 family regulates this release of AIF and subsequent caspase-independent cell death [12].
• Caspase-2 inhibitor benzyloxycarbonyl-Val-Asp-Val-Ala-Asp-fluoromethylketone or down-regulation of caspase-2 by its siRNA significantly prevented translocation of AIF [13].
• The other pathway, which is caspase-independent, involves AIF and leads to large-scale DNA fragmentation and peripheral chromatin condensation [14].
• AIFsh2 transcript includes a previously unknown exon placed between exons 9 and 10 of AIF [15].

Anatomical context of Aifm1

• Subcellular fractionation and immunofluorescence studies revealed cisplatin-induced translocation of AIF from the mitochondria to the nuclei [13].
• p53-dependent caspase-2 activation in mitochondrial release of apoptosis-inducing factor and its role in renal tubular epithelial cell injury [13].
• Calpeptin and the mitochondrial permeability transition pore antagonist cyclosporin A also inhibited calcium-induced AIF release from mouse liver mitochondria, implicating the involvement of an endogenous mitochondrial calpain in release of AIF during permeability transition [1].
• These results show that PA-induced podocyte apoptosis is p53 dependent and associated with changes in Bcl-2-related proteins and AIF translocation [16].
• Studies of primary mouse midbrain cultures further supported a role for AIF in caspase-independent cell death in MPP+-treated dopaminergic neurons [2].

Associations of Aifm1 with chemical compounds

• Enzymatic inhibition of calpain by calpeptin precluded AIF release, demonstrating that proteolytic activity was required for release [1].
• AIF translocation was inhibited by dexamethasone [16].
• Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death [17].
• 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 [18].
• 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 [4].
• Superoxide scavenging protects from AICD in wild-type, but not Hq, T cell blasts, suggesting that Aif plays a crucial superoxide-scavenging role to regulate T cell AICD [19].

Physical interactions of Aifm1

• Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor [20].

Enzymatic interactions of Aifm1

• Both precursor and mature forms of recombinant AIF were cleaved near the amino terminus by calpain I in vitro [1].

Regulatory relationships of Aifm1

• Caspase-2 and -3 that were predominantly activated in response to cisplatin provided a unique model to study the role of these caspases in AIF release [13].
• Because elevated intracellular calcium is one of the most ubiquitous features of neuronal cell death, this study tested the hypothesis that cleavage of AIF by the calcium-activated protease calpain mediates its release from mitochondria [1].
• These results demonstrate a novel mechanism whereby IL-4 and IL-13 can suppress mast cell development by inducing the production of an apoptosis-inducing factor from macrophages [21].
• Cell death induced by truncated Bid was inhibited by AIF siRNA, indicating that caspase-independent AIF signaling is the main pathway through which Bid mediates cell death [22].

Other interactions of Aifm1

• Pancaspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone or p53 inhibitor pifithrin-alpha markedly prevented mitochondrial release of AIF, suggesting that caspases and p53 are involved in this release [13].
• Taken together, these results define a novel mechanism of AIF release involving calpain processing and identify a potential molecular checkpoint for cytoprotective interventions [1].
• Podocyte apoptosis induced by PA was caspase-3 independent but was associated with the translocation of apoptosis-inducing factor (AIF) from the cytoplasm to nuclei [16].
• Microinjection of an antibody to AIF protects against PARP-1-dependent cytotoxicity [23].
• Increased immunoreactivities for manganese superoxide dismutase, cytochrome c oxidase I, and apoptosis-inducing factor in the inner segment indicated mitochondrial oxidative stress [24].

Analytical, diagnostic and therapeutic context of Aifm1

• Hsp70 specifically interacted with AIF, as shown by ligand blots and co-immunoprecipitation [25].
• In the subventricular zone (SVZ) and the granular cell layer (GCL) of the dentate gyrus, harboring neural and other progenitor cells, nitrosylation and p53 peaked 2-12 h after IR, followed by markers for active caspase-3, apoptosis-inducing factor and TUNEL (6-24 h) [26].
• Western blot analysis and immunofluorescent staining for cytochrome c and apoptosis-inducing factor (AIF) were performed [27].
• The translocation of AIF and endonuclease G correlated with mitochondrial dysfunction as indicated by the progressive loss of the mitochondrial membrane potential (measured with the JC-1 assay) and the appearance of nuclear DNA fragments in the cytosol (determined by an anti-histone ELISA) [28].
• The subcellular localization of AIF was examined by immunohistochemistry and immunoelectron microscopy [10].

References