title: Iron regulatory protein 1 sustains mitochondrial iron loading and function in frataxin deficiency.
abstract: Mitochondrial iron accumulation is a hallmark of diseases associated with impaired iron-sulfur cluster (Fe-S) biogenesis, such as Friedreich ataxia linked to frataxin (FXN) deficiency. The pathophysiological relevance of the mitochondrial iron loading and the underlying mechanisms are unknown. Using a mouse model of hepatic FXN deficiency in combination with mice deficient for iron regulatory protein 1 (IRP1), a key regulator of cellular iron metabolism, we show that IRP1 activation in conditions of Fe-S deficiency increases the available cytosolic labile iron pool. Surprisingly, our data indicate that IRP1 activation sustains mitochondrial iron supply and function rather than driving detrimental iron overload. Mitochondrial iron accumulation is shown to depend on mitochondrial dysfunction and heme-dependent upregulation of the mitochondrial iron importer mitoferrin-2. Our results uncover an unexpected protective role of IRP1 in pathological conditions associated with altered Fe-S metabolism.
authors: Translational Medecine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France; INSERM, U596, 67400 Illkirch, France; CNRS, UMR7104, 67400 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France; Collège de France, Chaire de génétique humaine, 67400 Illkirch, France. Electronic address: martelli@igbmc.fr.
authors: Alain
authors: A
authors: Martelli
authors: Translational Medecine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France; INSERM, U596, 67400 Illkirch, France; CNRS, UMR7104, 67400 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France; Collège de France, Chaire de génétique humaine, 67400 Illkirch, France.
authors: Stéphane
authors: S
authors: Schmucker
authors: Translational Medecine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France; INSERM, U596, 67400 Illkirch, France; CNRS, UMR7104, 67400 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France; Collège de France, Chaire de génétique humaine, 67400 Illkirch, France.
authors: Laurence
authors: L
authors: Reutenauer
authors: Institut Cochin, INSERM, U1016, CNRS, UMR8104, Université Paris Descartes, 75014 Paris, France.
authors: Jacques R R
authors: JRR
authors: Mathieu
authors: Institut Cochin, INSERM, U1016, CNRS, UMR8104, Université Paris Descartes, 75014 Paris, France.
authors: Carole
authors: C
authors: Peyssonnaux
authors: Inserm Unité 1149, Center for Research on Inflammation (CRI), Université Paris Diderot, Sorbonne Paris Cité, site Bichat, 75018 Paris, France.
authors: Zoubida
authors: Z
authors: Karim
authors: Inserm Unité 1149, Center for Research on Inflammation (CRI), Université Paris Diderot, Sorbonne Paris Cité, site Bichat, 75018 Paris, France; AP-HP, Centre Français des Porphyries, Hôpital Louis Mourier, 92701 Colombes, France.
authors: Hervé
authors: H
authors: Puy
authors: European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors: Bruno
authors: B
authors: Galy
authors: European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors: Matthias W
authors: MW
authors: Hentze
authors: Translational Medecine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France; INSERM, U596, 67400 Illkirch, France; CNRS, UMR7104, 67400 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France; Collège de France, Chaire de génétique humaine, 67400 Illkirch, France. Electronic address: hpuccio@igbmc.fr.
authors: Hélène
authors: H
authors: Puccio
mesh_terms: D000818:Animals; D005621:Friedreich Ataxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000172:deficiency / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D000096923:Frataxin
chemical_list: D007501:Iron; D035941:Iron Regulatory Protein 1; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D000096923:Frataxin