title: Mitochondrial energetic defects in muscle and brain of a Hmbs-/- mouse model of acute intermittent porphyria.
abstract: Acute intermittent porphyria (AIP), an autosomal dominant metabolic disease (MIM #176000), is due to a deficiency of hydroxymethylbilane synthase (HMBS), which catalyzes the third step of the heme biosynthetic pathway. The clinical expression of the disease is mainly neurological, involving the autonomous, central and peripheral nervous systems. We explored mitochondrial oxidative phosphorylation (OXPHOS) in the brain and skeletal muscle of the Hmbs(-/-) mouse model first in the basal state (BS), and then after induction of the disease with phenobarbital and treatment with heme arginate (HA). The modification of the respiratory parameters, determined in mice in the BS, reflected a spontaneous metabolic energetic adaptation to HMBS deficiency. Phenobarbital induced a sharp alteration of the oxidative metabolism with a significant decrease of ATP production in skeletal muscle that was restored by treatment with HA. This OXPHOS defect was due to deficiencies in complexes I and II in the skeletal muscle whereas all four respiratory chain complexes were affected in the brain. To date, the pathogenesis of AIP has been mainly attributed to the neurotoxicity of aminolevulinic acid and heme deficiency. Our results show that mitochondrial energetic failure also plays an important role in the expression of the disease.
authors.affiliation: UMR INSERM 1063, Département de Biochimie et Génétique and.
authors.forename: Chadi
authors.initials: C
authors.lastname: Homedan
authors.affiliation: Assistance Publique Hôpitaux de Paris, Centre Français des Porphyries, Hôpital Louis Mourier AP-HP, 178 rue des Renouillers, Colombes 92701, France, INSERM U1149, CNRS ERL 8252, Center for Research on Inflammation (CRI), Université Paris Diderot, site Bichat, Sorbonne Paris Cité, 16 rue Henri Huchard, Paris 75018, France and Laboratory of Excellence, GR-Ex, Sorbonne Paris Cité, 16 rue Henri Huchard, Paris 75018, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schmitt
authors.affiliation: UMR INSERM 1063.
authors.forename: Jihane
authors.initials: J
authors.lastname: Laafi
authors.affiliation: Département de Biochimie et Génétique and UMR CNRS 6214 - INSERM 1083, Centre Hospitalier Universitaire, 4 rue Larrey, Angers 49933, France.
authors.forename: Naïg
authors.initials: N
authors.lastname: Gueguen
authors.affiliation: Département de Biochimie et Génétique and UMR CNRS 6214 - INSERM 1083, Centre Hospitalier Universitaire, 4 rue Larrey, Angers 49933, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Desquiret-Dumas
authors.affiliation: INSERM U1149, CNRS ERL 8252, Center for Research on Inflammation (CRI), Université Paris Diderot, site Bichat, Sorbonne Paris Cité, 16 rue Henri Huchard, Paris 75018, France and Laboratory of Excellence, GR-Ex, Sorbonne Paris Cité, 16 rue Henri Huchard, Paris 75018, France.
authors.forename: Hugo
authors.initials: H
authors.lastname: Lenglet
authors.affiliation: INSERM U1149, CNRS ERL 8252, Center for Research on Inflammation (CRI), Université Paris Diderot, site Bichat, Sorbonne Paris Cité, 16 rue Henri Huchard, Paris 75018, France and Laboratory of Excellence, GR-Ex, Sorbonne Paris Cité, 16 rue Henri Huchard, Paris 75018, France.
authors.forename: Zoubida
authors.initials: Z
authors.lastname: Karim
authors.affiliation: Assistance Publique Hôpitaux de Paris, Centre Français des Porphyries, Hôpital Louis Mourier AP-HP, 178 rue des Renouillers, Colombes 92701, France, INSERM U1149, CNRS ERL 8252, Center for Research on Inflammation (CRI), Université Paris Diderot, site Bichat, Sorbonne Paris Cité, 16 rue Henri Huchard, Paris 75018, France and Laboratory of Excellence, GR-Ex, Sorbonne Paris Cité, 16 rue Henri Huchard, Paris 75018, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.affiliation: Assistance Publique Hôpitaux de Paris, Centre Français des Porphyries, Hôpital Louis Mourier AP-HP, 178 rue des Renouillers, Colombes 92701, France, INSERM U1149, CNRS ERL 8252, Center for Research on Inflammation (CRI), Université Paris Diderot, site Bichat, Sorbonne Paris Cité, 16 rue Henri Huchard, Paris 75018, France and Laboratory of Excellence, GR-Ex, Sorbonne Paris Cité, 16 rue Henri Huchard, Paris 75018, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Deybach
authors.affiliation: UMR INSERM 1063, Département de Biochimie et Génétique and.
authors.forename: Gilles
authors.initials: G
authors.lastname: Simard
authors.affiliation: Assistance Publique Hôpitaux de Paris, Centre Français des Porphyries, Hôpital Louis Mourier AP-HP, 178 rue des Renouillers, Colombes 92701, France, INSERM U1149, CNRS ERL 8252, Center for Research on Inflammation (CRI), Université Paris Diderot, site Bichat, Sorbonne Paris Cité, 16 rue Henri Huchard, Paris 75018, France and Laboratory of Excellence, GR-Ex, Sorbonne Paris Cité, 16 rue Henri Huchard, Paris 75018, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Puy
authors.affiliation: UMR INSERM 1063, Département de Biochimie et Génétique and.
authors.forename: Yves
authors.initials: Y
authors.lastname: Malthièry
authors.affiliation: Département de Biochimie et Génétique and UMR CNRS 6214 - INSERM 1083, Centre Hospitalier Universitaire, 4 rue Larrey, Angers 49933, France, pareynier@chu-angers.fr.
authors.forename: Pascal
authors.initials: P
authors.lastname: Reynier
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D009132:Muscles / Q000187:drug effects / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D017118:Porphyria, Acute Intermittent / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; D011163:Hydroxymethylbilane Synthase; D042967:Electron Transport Complex I; D010634:Phenobarbital