title: Reduction of Na+, K+-ATPase activity and expression in cerebral cortex of glutaryl-CoA dehydrogenase deficient mice: a possible mechanism for brain injury in glutaric aciduria type I.
abstract: Mitochondrial dysfunction has been proposed to play an important role in the neuropathology of glutaric acidemia type I (GA I). However, the relevance of bioenergetics disruption and the exact mechanisms responsible for the cortical leukodystrophy and the striatum degeneration presented by GA I patients are not yet fully understood. Therefore, in the present work we measured the respiratory chain complexes activities I-IV, mitochondrial respiratory parameters state 3, state 4, the respiratory control ratio and dinitrophenol (DNP)-stimulated respiration (uncoupled state), as well as the activities of α-ketoglutarate dehydrogenase (α-KGDH), creatine kinase (CK) and Na+, K+-ATPase in cerebral cortex, striatum and hippocampus from 30-day-old Gcdh-/- and wild type (WT) mice fed with a normal or a high Lys (4.7%) diet. When a baseline (0.9% Lys) diet was given, we verified mild alterations of the activities of some respiratory chain complexes in cerebral cortex and hippocampus, but not in striatum from Gcdh-/- mice as compared to WT animals. Furthermore, the mitochondrial respiratory parameters and the activities of α-KGDH and CK were not modified in all brain structures from Gcdh-/- mice. In contrast, we found a significant reduction of Na(+), K(+)-ATPase activity associated with a lower degree of its expression in cerebral cortex from Gcdh-/- mice. Furthermore, a high Lys (4.7%) diet did not accentuate the biochemical alterations observed in Gcdh-/- mice fed with a normal diet. Since Na(+), K(+)-ATPase activity is required for cell volume regulation and to maintain the membrane potential necessary for a normal neurotransmission, it is presumed that reduction of this enzyme activity may represent a potential underlying mechanism involved in the brain swelling and cortical abnormalities (cortical atrophy with leukodystrophy) observed in patients affected by GA I.
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.forename: Bianca
authors.initials: B
authors.lastname: Seminotti
authors.forename: Cristiane
authors.initials: C
authors.lastname: Cecatto
authors.forename: Carolina Gonçalves
authors.initials: CG
authors.lastname: Fernandes
authors.forename: Estela Natacha Brandt
authors.initials: EN
authors.lastname: Busanello
authors.forename: Ângela
authors.initials: Â
authors.lastname: Zanatta
authors.forename: Luiza Wilges
authors.initials: LW
authors.lastname: Kist
authors.forename: Maurício Reis
authors.initials: MR
authors.lastname: Bogo
authors.forename: Diogo Onofre Gomes
authors.initials: DO
authors.lastname: de Souza
authors.forename: Michael
authors.initials: M
authors.lastname: Woontner
authors.forename: Stephen
authors.initials: S
authors.lastname: Goodman
authors.forename: David M
authors.initials: DM
authors.lastname: Koeller
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001928:Brain Diseases, Metabolic / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology*; D003342:Corpus Striatum / Q000201:enzymology / Q000473:pathology*; D003402:Creatine Kinase / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004579:Electron Transport / Q000235:genetics; D005526:Food, Formulated; D015870:Gene Expression; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism
chemical_list: D007655:Ketoglutarate Dehydrogenase Complex; D050770:Glutaryl-CoA Dehydrogenase; D003402:Creatine Kinase; D000254:Sodium-Potassium-Exchanging ATPase