title: Redox reactions of the FAD-containing apoptosis-inducing factor (AIF) with quinoidal xenobiotics: a mechanistic study.
abstract: Mitochondrial apoptosis-inducing factor (AIF) is a FAD-containing protein that under certain conditions translocates to the nucleus and causes a programmed cell death, apoptosis. The apoptogenic action of AIF is redox controlled as the NADH-reduced AIF dimer has lower affinity for DNA than the oxidized monomer. To gain further insights into the mechanism of AIF, we investigated its interaction with a series of quinone oxidants, including a number of anticancer quinones. Our data indicate that the NADH:quinone oxidoreduction catalyzed by AIF follows a "ping-pong" scheme, with the reductive half-reaction being rate-limiting and the FADH(-)-NAD(+) charge-transfer complex serving as an electron donor. AIF is equally reactive toward benzo- and naphthoquinones, but may discriminate structures with a higher number of aromatic rings. The reactivity of quinones is mainly defined by their one-electron reduction potential, whereas the size and nature of the substituents play a minor role. AIF is unlikely to significantly contribute to bioreductive activation of low-potential quinoidal anticancer quinones. However, high-potential quinones, e.g. a toxic natural compound naphthazarin, maintain AIF in the oxidized state when a significant excess of NADH is present. Thus, these compounds may prevent the accumulation of the reduced form of AIF in vivo, and enhance AIF-mediated apoptosis.
authors.affiliation: Institute of Biochemistry of Vilnius University, Mokslininkų, Lithuania.
authors.forename: Lina
authors.initials: L
authors.lastname: Misevičienė
authors.forename: Zilvinas
authors.initials: Z
authors.lastname: Anusevičius
authors.forename: Jonas
authors.initials: J
authors.lastname: Sarlauskas
authors.forename: Irina F
authors.initials: IF
authors.lastname: Sevrioukova
authors.forename: Narimantas
authors.initials: N
authors.lastname: Cėnas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051033:Apoptosis Inducing Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005182:Flavin-Adenine Dinucleotide / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D011809:Quinones / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D016877:Oxidants; D011809:Quinones; D011994:Recombinant Proteins; D015262:Xenobiotics; D005182:Flavin-Adenine Dinucleotide