title: The diabetes drug target MitoNEET governs a novel trafficking pathway to rebuild an Fe-S cluster into cytosolic aconitase/iron regulatory protein 1.
abstract: In eukaryotes, mitochondrial iron-sulfur cluster (ISC), export and cytosolic iron-sulfur cluster assembly (CIA) machineries carry out biogenesis of iron-sulfur (Fe-S) clusters, which are critical for multiple essential cellular pathways. However, little is known about their export out of mitochondria. Here we show that Fe-S assembly of mitoNEET, the first identified Fe-S protein anchored in the mitochondrial outer membrane, strictly depends on ISC machineries and not on the CIA or CIAPIN1. We identify a dedicated ISC/export pathway in which augmenter of liver regeneration, a mitochondrial Mia40-dependent protein, is specific to mitoNEET maturation. When inserted, the Fe-S cluster confers mitoNEET folding and stability in vitro and in vivo. The holo-form of mitoNEET is resistant to NO and H2O2 and is capable of repairing oxidatively damaged Fe-S of iron regulatory protein 1 (IRP1), a master regulator of cellular iron that has recently been involved in the mitochondrial iron supply. Therefore, our findings point to IRP1 as the missing link to explain the function of mitoNEET in the control of mitochondrial iron homeostasis.
authors.affiliation: From the Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, 91190 Gif-sur-Yvette, France.
authors.forename: Ioana
authors.initials: I
authors.lastname: Ferecatu
authors.affiliation: From the Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, 91190 Gif-sur-Yvette, France.
authors.forename: Sergio
authors.initials: S
authors.lastname: Gonçalves
authors.affiliation: From the Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, 91190 Gif-sur-Yvette, France, the Institut Jacques Monod, CNRS, UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Golinelli-Cohen
authors.affiliation: the Direction des Sciences du Vivant, Institute of Life Sciences Research and Technologies, Chemistry and Biology of Metals Laboratory, UMR 5249 CEA-Université Grenoble I-CNRS/Equipe de Physicochimie des Métaux en Biologie, CEA-Grenoble, 17 rue des Martyrs, 38054 Grenoble Cedex 09, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Clémancey
authors.affiliation: the Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), F-67400 Illkirch, France, the INSERM, U596, Illkirch, France, the CNRS, UMR7104, Illkirch, France, the Université de Strasbourg, F-67000 Strasbourg, France, the Collège de France, Chaire de Génétique Humaine, Illkirch, France, and.
authors.forename: Alain
authors.initials: A
authors.lastname: Martelli
authors.affiliation: From the Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, 91190 Gif-sur-Yvette, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Riquier
authors.affiliation: From the Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, 91190 Gif-sur-Yvette, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Guittet
authors.affiliation: the Direction des Sciences du Vivant, Institute of Life Sciences Research and Technologies, Chemistry and Biology of Metals Laboratory, UMR 5249 CEA-Université Grenoble I-CNRS/Equipe de Physicochimie des Métaux en Biologie, CEA-Grenoble, 17 rue des Martyrs, 38054 Grenoble Cedex 09, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Latour
authors.affiliation: the Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), F-67400 Illkirch, France, the INSERM, U596, Illkirch, France, the CNRS, UMR7104, Illkirch, France, the Université de Strasbourg, F-67000 Strasbourg, France, the Collège de France, Chaire de Génétique Humaine, Illkirch, France, and.
authors.forename: Hélène
authors.initials: H
authors.lastname: Puccio
authors.affiliation: From the Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, 91190 Gif-sur-Yvette, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Drapier
authors.affiliation: From the Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, 91190 Gif-sur-Yvette, France.
authors.forename: Ewen
authors.initials: E
authors.lastname: Lescop
authors.affiliation: From the Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, 91190 Gif-sur-Yvette, France, cecile.bouton@cnrs.fr.
authors.forename: Cécile
authors.initials: C
authors.lastname: Bouton
mesh_terms: D000818:Animals; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000737:chemistry / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry; D010084:Oxidation-Reduction; D017510:Protein Folding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C507282:CHCHD4 protein, human; C525595:CISD1 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D007501:Iron; C546175:ACO1 protein, human; D035941:Iron Regulatory Protein 1
keywords: Fe-S Transfer; Iron Metabolism; Iron Regulatory Protein 1; Iron-Sulfur Protein; MitoNEET; Mitochondria; Nitric Oxide; Oxidative Stress; Protein Degradation; Small Interfering RNA (siRNA)