title: Inhibition of energy metabolism in cerebral cortex of young rats by the medium-chain fatty acids accumulating in MCAD deficiency.
abstract: Patients affected by medium-chain acyl CoA dehydrogenase (MCAD) deficiency, a frequent inborn error of metabolism, suffer from acute episodes of encephalopathy. However, the mechanisms underlying the neuropathology of this disease are poorly known. In the present study, we investigated the in vitro effect of the medium-chain fatty acids (MCFA), at concentrations varying from 0.01 to 3 mM, accumulating in MCAD deficiency on some parameters of energy metabolism in cerebral cortex of young rats. (14)CO(2) production from [U(14)] glucose, [1-(14)C] acetate and [1,5-(14)C] citrate was evaluated by incubating cerebral cortex homogenates from 30-day-old rats in the absence (controls) or presence of octanoic acid, decanoic acid or cis-4-decenoic acid. OA and DA significantly reduced (14)CO(2) production from acetate by around 30-40%, and from glucose by around 70%. DA significantly reduced (14)CO(2) production from citrate by around 40%, while OA did not affect this parameter. cDA inhibited (14)CO(2) production from all tested substrates by around 30-40%. The activities of the respiratory chain complexes and of creatine kinase were also tested in the presence of DA and cDA. Both metabolites significantly inhibited cytochrome c oxidase activity (by 30%) and complex II-III activity (DA, 25%; cDA, 80%). Furthermore, only cDA inhibited complex II activity (by 30%), while complex I-III and citrate synthase were not affected by these MCFA. On the other hand, only cDA reduced the activity of creatine kinase in total homogenates, as well as in mitochondrial and cytosolic fractions from cerebral cortex (by 50%). The data suggest that the major metabolites which accumulate in MCAD deficiency, with particular emphasis to cDA, compromise brain energy metabolism. We presume that these findings may contribute to the understanding of the pathophysiology of the neurological dysfunction of MCAD deficient patients.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 90035-003, Brazil.
authors.forename: Dênis
authors.initials: D
authors.lastname: Reis de Assis
authors.forename: Rita de Cássia
authors.initials: Rde C
authors.lastname: Maria
authors.forename: Rafael
authors.initials: R
authors.lastname: Borba Rosa
authors.forename: Patrícia Fernanda
authors.initials: PF
authors.lastname: Schuck
authors.forename: César Augusto João
authors.initials: CA
authors.lastname: Ribeiro
authors.forename: Gustavo
authors.initials: G
authors.lastname: da Costa Ferreira
authors.forename: Carlos Severo
authors.initials: CS
authors.lastname: Dutra-Filho
authors.forename: Angela
authors.initials: A
authors.lastname: Terezinha de Souza Wyse
authors.forename: Clóvis Milton
authors.initials: CM
authors.lastname: Duval Wannmacher
authors.forename: Marcos Luiz
authors.initials: ML
authors.lastname: Santos Perry
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000085:Acetates / Q000378:metabolism; D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency*; D000367:Age Factors; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D002210:Caprylates / Q000494:pharmacology; D002250:Carbon Radioisotopes; D002540:Cerebral Cortex / Q000378:metabolism*; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D003652:Decanoic Acids / Q000494:pharmacology; D004579:Electron Transport / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism*; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000085:Acetates; D000935:Antifungal Agents; D000959:Antihypertensive Agents; D002210:Caprylates; D002250:Carbon Radioisotopes; D003652:Decanoic Acids; D005227:Fatty Acids; C031071:decanoic acid; D042964:Acyl-CoA Dehydrogenase; D002950:Citrate (si)-Synthase; D003402:Creatine Kinase; C031492:octanoic acid