title: Apoptosis inducing factor (AIF) mediates lethal redox stress induced by menadione.
abstract: Mitochondrial apoptosis inducing factor (AIF) is a redox-active enzyme that participates to the biogenesis/maintenance of complex I of the respiratory chain, yet also contributes to catabolic reactions in the context of regulated cell death when AIF translocates to the cytosol and to the nucleus. Here we explore the contribution of AIF to cell death induced by menadione (2-methyl-1,4-naphtoquinone; also called vitamin K3) in conditions in which this pro-oxidant does not cause the mitochondrial release of AIF, yet causes caspase-independent cell killing. Depletion of AIF from human cancer cells reduced the cytotoxicity of menadione. This cytoprotective effect was accompanied by the maintenance of high levels of reduced glutathione (GSH), which are normally depleted by menadione. In addition, AIF depletion reduced the arylation of cellular proteins induced by menadione. This menadione-triggered arylation, which can be measured by a fluorescence assay, is completely suppressed by addition of exogenous glutathione or N-acetyl cysteine. Complex I inhibition by Rotenone did not mimic the cytoprotective action of AIF depletion. Altogether, these results are compatible with the hypothesis that mitochondrion-sessile AIF facilitates lethal redox cycling of menadione, thereby precipitating protein arylation and glutathione depletion.
authors.affiliation: Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|INSERM, U1138, Paris, France.|Gustave Roussy Cancer Campus, Villejuif, France.|Faculty of Medicine, Université Paris-Saclay, Kremlin-Bicêtre, France.|Institut Teknologi Bandung (ITB), Bandung, Indonesia.
authors.forename: Hesti Lina
authors.initials: HL
authors.lastname: Wiraswati
authors.affiliation: Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|INSERM, U1138, Paris, France.|Gustave Roussy Cancer Campus, Villejuif, France.|Faculty of Medicine, Université Paris-Saclay, Kremlin-Bicêtre, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Hangen
authors.affiliation: Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|INSERM, U1138, Paris, France.|Gustave Roussy Cancer Campus, Villejuif, France.|Faculty of Medicine, Université Paris-Saclay, Kremlin-Bicêtre, France.|Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz UAM and REDINREN, Madrid, Spain.
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: Sanz
authors.affiliation: Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|INSERM, U1138, Paris, France.|Gustave Roussy Cancer Campus, Villejuif, France.|Faculty of Medicine, Université Paris-Saclay, Kremlin-Bicêtre, France.
authors.forename: Ngoc-Vy
authors.initials: NV
authors.lastname: Lam
authors.affiliation: Gustave Roussy Cancer Campus, Villejuif, France.|Faculty of Medicine, Université Paris-Saclay, Kremlin-Bicêtre, France.|INSERM, U1030, Villejuif, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Reinhardt
authors.affiliation: Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|INSERM, U1138, Paris, France.|Gustave Roussy Cancer Campus, Villejuif, France.|Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Allan
authors.initials: A
authors.lastname: Sauvat
authors.affiliation: Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|INSERM, U1138, Paris, France.|Gustave Roussy Cancer Campus, Villejuif, France.|Faculty of Medicine, Université Paris-Saclay, Kremlin-Bicêtre, France.
authors.forename: Ariane
authors.initials: A
authors.lastname: Mogha
authors.affiliation: Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz UAM and REDINREN, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|INSERM, U1138, Paris, France.|Gustave Roussy Cancer Campus, Villejuif, France.|Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.|Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.|Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Gustave Roussy Cancer Campus, Villejuif, France.|Faculty of Medicine, Université Paris-Saclay, Kremlin-Bicêtre, France.|INSERM, U1030, Villejuif, France.
authors.forename: Nazanine
authors.initials: N
authors.lastname: Modjtahedi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000235:genetics* / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics*; D024483:Vitamin K 3 / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D051033:Apoptosis Inducing Factor; D024483:Vitamin K 3; D005978:Glutathione
keywords: Autophagy; mitochondria; oxidative stress; protein arylation; quinone metabolization