title: The oxido-reductase activity of the apoptosis inducing factor: a promising pharmacological tool?
abstract: The apoptosis inducing factor (AIF) was first discovered as a caspase-independent apoptosis effector that promoted cell death upon release from the mitochondria (triggered by pro-apoptotic stimuli) and relocalization into the nucleus, where it promotes chromatin condensation and DNA fragmentation. AIF is a mammalian mitochondrial FAD-dependent flavoenzyme, ubiquitous in vertebrate cells,and with orthologs in all eukaryotes. Beyond its role in apoptosis AIF has additional functions in mitochondria, mainly related with the redox function of its flavin adenine dinucleotide cofactor (FAD), which despite being poorly understood are vital. Thus, defects in AIF trigger major dysfunctions in oxidative phosphorylation, and cause severe illnesses related with neurodegeneration as a consequence of mitochondriopathies. AIF folds in three modules: a FAD-binding, a nicotine adenine dinucleotide (NADH)-binding and a C-terminal modules. Upon reduction of the flavin cofactor by NADH, conformational changes leading to AIF dimerization are proposed as a key early event in the mitochondrial sensing/signaling functions of AIF. The recent interest in the design of new therapies to modulate caspase-independent apoptosis pathways also makes AIF a potential pharmacological target to treat pathological disorders related with AIF dependent mitochondriopathies. Therefore, the first step in this direction must be to understand the molecular basis of the AIF redox reactions and their relationship with the apoptotic function. Here, we examine recent research towards the molecular mechanisms linked to the AIF oxido-reduction properties.
authors.affiliation: Department of Biochemistry, and Institute for Biocomputation and Physics of Complex Systems, University of Zaragoza, Zaragoza, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ferreira
authors.forename: Raquel
authors.initials: R
authors.lastname: Villanueva
authors.forename: Lauriane
authors.initials: L
authors.lastname: Cabon
authors.forename: Santos A
authors.initials: SA
authors.lastname: Susín
authors.forename: Milagros
authors.initials: M
authors.lastname: Medina
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051033:Apoptosis Inducing Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D053938:DNA Fragmentation; D055808:Drug Discovery; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D016415:Sequence Alignment
chemical_list: D051033:Apoptosis Inducing Factor; D010088:Oxidoreductases