title: Acute intermittent porphyria causes hepatic mitochondrial energetic failure in a mouse model.
abstract: Acute intermittent porphyria (AIP), an inherited hepatic disorder, is due to a defect of hydroxymethylbilane synthase (HMBS), an enzyme involved in heme biosynthesis. AIP is characterized by recurrent, life-threatening attacks at least partly due to the increased hepatic production of 5-aminolaevulinic acid (ALA). Both the mitochondrial enzyme, ALA synthase (ALAS) 1, involved in the first step of heme biosynthesis, which is closely linked to mitochondrial bioenergetic pathways, and the promise of an ALAS1 siRNA hepatic therapy in humans, led us to investigate hepatic energetic metabolism in Hmbs KO mice treated with phenobarbital. The mitochondrial respiratory chain (RC) and the tricarboxylic acid (TCA) cycle were explored in the Hmbs(-/-) mouse model. RC and TCA cycle were significantly affected in comparison to controls in mice treated with phenobarbital with decreased activities of RC complexes I (-52%, (**)p<0.01), II (-50%, (**)p<0.01) and III (-55%, (*)p<0.05), and decreased activity of α-ketoglutarate dehydrogenase (-64%, (*)p<0.05), citrate synthase (-48%, (**)p<0.01) and succinate dehydrogenase (-53%, (*)p<0.05). Complex II-driven succinate respiration was also significantly affected. Most of these metabolic alterations were at least partially restored after the phenobarbital arrest and heme arginate administration. These results suggest a cataplerosis of the TCA cycle induced by phenobarbital, caused by the massive withdrawal of succinyl-CoA by ALAS induction, such that the TCA cycle is unable to supply the reduced cofactors to the RC. This profound and reversible impact of AIP on mitochondrial energetic metabolism offers new insights into the beneficial effect of heme, glucose and ALAS1 siRNA treatments by limiting the cataplerosis of TCA cycle.
authors.affiliation: UMR INSERM 1063, Angers, France; Centre Hospitalier Universitaire, Département de Biochimie et Génétique, Angers, France.
authors.forename: Chadi
authors.initials: C
authors.lastname: Homedan
authors.affiliation: UMR INSERM 1063, Angers, France.
authors.forename: Jihane
authors.initials: J
authors.lastname: Laafi
authors.affiliation: Assistance Publique Hôpitaux de Paris, Centre Français des Porphyries, Hôpital Louis Mourier, Université Paris Diderot, Colombes, France; INSERM U1149, Center for Research on Inflammation (CRI), Université Paris Diderot, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schmitt
authors.affiliation: Centre Hospitalier Universitaire, Département de Biochimie et Génétique, Angers, France; UMR CNRS 6214-INSERM 1083, Angers, France.
authors.forename: Naïg
authors.initials: N
authors.lastname: Gueguen
authors.affiliation: Assistance Publique Hôpitaux de Paris, Centre Français des Porphyries, Hôpital Louis Mourier, Université Paris Diderot, Colombes, France; INSERM U1149, Center for Research on Inflammation (CRI), Université Paris Diderot, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Thibaud
authors.initials: T
authors.lastname: Lefebvre
authors.affiliation: Assistance Publique Hôpitaux de Paris, Centre Français des Porphyries, Hôpital Louis Mourier, Université Paris Diderot, Colombes, France; INSERM U1149, Center for Research on Inflammation (CRI), Université Paris Diderot, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Zoubida
authors.initials: Z
authors.lastname: Karim
authors.affiliation: Centre Hospitalier Universitaire, Département de Biochimie et Génétique, Angers, France; UMR CNRS 6214-INSERM 1083, Angers, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Desquiret-Dumas
authors.affiliation: Centre Hospitalier Universitaire, Département de Biochimie et Génétique, Angers, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Wetterwald
authors.affiliation: Assistance Publique Hôpitaux de Paris, Centre Français des Porphyries, Hôpital Louis Mourier, Université Paris Diderot, Colombes, France; INSERM U1149, Center for Research on Inflammation (CRI), Université Paris Diderot, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Deybach
authors.affiliation: Assistance Publique Hôpitaux de Paris, Centre Français des Porphyries, Hôpital Louis Mourier, Université Paris Diderot, Colombes, France; INSERM U1149, Center for Research on Inflammation (CRI), Université Paris Diderot, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.affiliation: Assistance Publique Hôpitaux de Paris, Centre Français des Porphyries, Hôpital Louis Mourier, Université Paris Diderot, Colombes, France; INSERM U1149, Center for Research on Inflammation (CRI), Université Paris Diderot, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Puy
authors.affiliation: Centre Hospitalier Universitaire, Département de Biochimie et Génétique, Angers, France; UMR CNRS 6214-INSERM 1083, Angers, France. Electronic address: pareynier@chu-angers.fr.
authors.forename: Pascal
authors.initials: P
authors.lastname: Reynier
authors.affiliation: UMR INSERM 1063, Angers, France; Centre Hospitalier Universitaire, Département de Biochimie et Génétique, Angers, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Malthièry
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005260:Female; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D017118:Porphyria, Acute Intermittent / Q000150:complications* / Q000378:metabolism
keywords: Acute intermittent porphyria; Hydroxymethylbilane synthase; Mitochondria; Oxidative phosphorylation; Tricarboxylic acid cycle