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Article Dans Une Revue Human Molecular Genetics Année : 2015

Mitochondrial energetic defects in muscle and brain of a Hmbs-/- mouse model of acute intermittent porphyria

Chadi Homedan
  • Fonction : Auteur
Caroline Schmitt
  • Fonction : Auteur
Jihane Laafi
  • Fonction : Auteur
Hugo Lenglet
  • Fonction : Auteur
Zoubida Karim
Laurent Gouya
  • Fonction : Auteur
Jean-Charles Deybach
  • Fonction : Auteur
Gilles Simard
  • Fonction : Auteur
  • PersonId : 935822
Hervé Puy
  • Fonction : Auteur
Yves Malthièry
  • Fonction : Auteur
  • PersonId : 930960

Résumé

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.

Dates et versions

hal-02056592 , version 1 (04-03-2019)

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Chadi Homedan, Caroline Schmitt, Jihane Laafi, Naïg Gueguen, Valérie Desquiret-Dumas, et al.. Mitochondrial energetic defects in muscle and brain of a Hmbs-/- mouse model of acute intermittent porphyria. Human Molecular Genetics, 2015, 24 (17), pp.5015-23. ⟨10.1093/hmg/ddv222⟩. ⟨hal-02056592⟩
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