title: Experimental evidence that bioenergetics disruption is not mainly involved in the brain injury of glutaryl-CoA dehydrogenase deficient mice submitted to lysine overload.
abstract: Bioenergetics dysfunction has been postulated as an important pathomechanism of brain damage in glutaric aciduria type I, but this is still under debate. We investigated activities of citric acid cycle (CAC) enzymes, lactate release, respiration and membrane potential (ΔΨm) in mitochondrial preparations from cerebral cortex and striatum of 30-day-old glutaryl-CoA dehydrogenase deficient (Gcdh-/-) and wild type mice fed a baseline or a high lysine (Lys, 4.7%) chow for 60 or 96h. Brain histological analyses were performed in these animals, as well as in 90-day-old animals fed a baseline or a high Lys chow during 30 days starting at 60-day-old. A moderate reduction of citrate synthase and isocitrate dehydrogenase activities was observed only in the striatum from 30-day-old Gcdh-/- animals submitted to a high Lys chow. In contrast, the other CAC enzyme activities, lactate release, the respiratory parameters state 3, state 4, the respiratory control ratio and CCCP-stimulated (uncoupled) state, as well as ΔΨm were not altered in the striatum. Similarly, none of the evaluated parameters were changed in the cerebral cortex from these animals under baseline or Lys overload. On the other hand, histological analyses revealed the presence of intense vacuolation in the cerebral cortex of 60 and 90-day-old Gcdh-/- mice fed a baseline chow and in the striatum of 90-day-old Gcdh-/- mice submitted to Lys overload for 30 days. Taken together, the present data demonstrate mild impairment of bioenergetics homeostasis and marked histological alterations in striatum from Gcdh-/- mice under a high Lys chow, suggesting that disruption of energy metabolism is not mainly involved in the brain injury of these animals.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Alexandre Umpierrez
authors.initials: AU
authors.lastname: Amaral
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Cristiane
authors.initials: C
authors.lastname: Cecatto
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Bianca
authors.initials: B
authors.lastname: Seminotti
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: César Augusto
authors.initials: CA
authors.lastname: Ribeiro
authors.affiliation: Serviço de Terapia Gênica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Valeska Lizzi
authors.initials: VL
authors.lastname: Lagranha
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Carolina Coffi
authors.initials: CC
authors.lastname: Pereira
authors.affiliation: Servico de Patologia, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Francine Hehn
authors.initials: FH
authors.lastname: de Oliveira
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Diogo Gomes
authors.initials: DG
authors.lastname: de Souza
authors.affiliation: School Medicine University of Colorado Denver, Aurora, CO, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Goodman
authors.affiliation: School Medicine University of Colorado Denver, Aurora, CO, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Woontner
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil. Electronic address: mwajner@ufrgs.br.
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism*; D000818:Animals; D001927:Brain Diseases / Q000378:metabolism* / Q000473:pathology; D001928:Brain Diseases, Metabolic / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004032:Diet; D004195:Disease Models, Animal; D004734:Energy Metabolism; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008239:Lysine / Q000008:administration & dosage*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D010101:Oxygen Consumption / Q000502:physiology
chemical_list: D019344:Lactic Acid; D007521:Isocitrate Dehydrogenase; D050770:Glutaryl-CoA Dehydrogenase; D008239:Lysine
keywords: Bioenergetics homeostasis; Brain histopathology; Citric acid cycle; Gcdh−/− mice; Glutaric acid; Glutaric acidemia type I