title: In vivo evidence of mitochondrial dysfunction and altered redox homeostasis in a genetic mouse model of propionic acidemia: Implications for the pathophysiology of this disorder.
abstract: Accumulation of toxic metabolites has been described to inhibit mitochondrial enzymes, thereby inducing oxidative stress in propionic acidemia (PA), an autosomal recessive metabolic disorder caused by the deficiency of mitochondrial propionyl-CoA carboxylase. PA patients exhibit neurological deficits and multiorgan complications including cardiomyopathy. To investigate the role of mitochondrial dysfunction in the development of these alterations we have used a hypomorphic mouse model of PA that mimics the biochemical and clinical hallmarks of the disease. We have studied the tissue-specific bioenergetic signature by Reverse Phase Protein Microarrays and analysed OXPHOS complex activities, mtDNA copy number, oxidative damage, superoxide anion and hydrogen peroxide levels. The results show decreased levels and/or activity of several OXPHOS complexes in different tissues of PA mice. An increase in mitochondrial mass and OXPHOS complexes was observed in brain, possibly reflecting a compensatory mechanism including metabolic reprogramming. mtDNA depletion was present in most tissues analysed. Antioxidant enzymes were also found altered. Lipid peroxidation was present along with an increase in hydrogen peroxide and superoxide anion production. These data support the hypothesis that oxidative damage may contribute to the pathophysiology of PA, opening new avenues in the identification of therapeutic targets and paving the way for in vivo evaluation of compounds targeting mitochondrial biogenesis or reactive oxygen species production.
authors.affiliation: Centro de Biología Molecular Severo Ochoa UAM-CSIC, Universidad Autónoma, Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Gallego-Villar
authors.affiliation: Centro de Biología Molecular Severo Ochoa UAM-CSIC, Universidad Autónoma, Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Rivera-Barahona
authors.affiliation: Centro de Biología Molecular Severo Ochoa UAM-CSIC, Universidad Autónoma, Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Cuevas-Martín
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Guenzel
authors.affiliation: Centro de Biología Molecular Severo Ochoa UAM-CSIC, Universidad Autónoma, Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Madrid, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Pérez
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Barry
authors.affiliation: Medical Research Council, Mitochondrial Biology Unit, Cambridge, UK.
authors.forename: M P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Medical Research Council, Mitochondrial Biology Unit, Cambridge, UK.
authors.forename: A
authors.initials: A
authors.lastname: Logan
authors.affiliation: CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gonzalez-Quintana
authors.affiliation: CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Martín
authors.affiliation: Department of Food Science and Technology, CEBAS-CSIC, Campus de Espinardo 25, 30100 Espinardo, Murcia, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Medina
authors.affiliation: Department of Food Science and Technology, CEBAS-CSIC, Campus de Espinardo 25, 30100 Espinardo, Murcia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gil-Izquierdo
authors.affiliation: Centro de Biología Molecular Severo Ochoa UAM-CSIC, Universidad Autónoma, Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Cuezva
authors.affiliation: Centro de Biología Molecular Severo Ochoa UAM-CSIC, Universidad Autónoma, Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Richard
authors.affiliation: Centro de Biología Molecular Severo Ochoa UAM-CSIC, Universidad Autónoma, Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Madrid, Spain. Electronic address: lruiz@cbm.csic.es.
authors.forename: L R
authors.initials: LR
authors.lastname: Desviat
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D004195:Disease Models, Animal; D006706:Homeostasis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation / Q000235:genetics; D043586:Methylmalonyl-CoA Decarboxylase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics*; D056693:Propionic Acidemia / Q000235:genetics* / Q000473:pathology; D040081:Protein Array Analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D013481:Superoxides; D006861:Hydrogen Peroxide; D043586:Methylmalonyl-CoA Decarboxylase
keywords: Antioxidant; Inherited metabolic diseases; Lipid peroxidation; MitoB; Mitochondria; Mouse models; OXPHOS; Oxidative damage; Propionic acidemia; ROS; Reverse phase protein microarrays; oxidative stress