title: Inhibition of brain energy metabolism by the alpha-keto acids accumulating in maple syrup urine disease.
abstract: Neurological dysfunction is a common finding in patients with maple syrup urine disease (MSUD). However, the mechanisms underlying the neuropathology of brain damage in this disorder are poorly known. In the present study, we investigated the effect of the in vitro effect of the branched chain alpha-keto acids (BCKA) accumulating in MSUD on some parameters of energy metabolism in cerebral cortex of rats. [14CO(2)] production from [14C] acetate, glucose uptake and lactate release from glucose were evaluated by incubating cortical prisms from 30-day-old rats in Krebs-Ringer bicarbonate buffer, pH 7.4, in the absence (controls) or presence of 1-5 mM of alpha-ketoisocaproic acid (KIC), alpha-keto-beta-methylvaleric acid (KMV) or alpha-ketoisovaleric acid (KIV). All keto acids significantly reduced 14CO(2) production by around 40%, in contrast to lactate release and glucose utilization, which were significantly increased by the metabolites by around 42% in cortical prisms. Furthermore, the activity of the respiratory chain complex I-III was significantly inhibited by 60%, whereas the other activities of the electron transport chain, namely complexes II, II-III, III and IV, as well as succinate dehydrogenase were not affected by the keto acids. The results indicate that the major metabolites accumulating in MSUD compromise brain energy metabolism by blocking the respiratory chain. We presume that these findings may be of relevance to the understanding of the pathophysiology of the neurological dysfunction of MSUD patients.
authors.affiliation: Departamento de Bioqui;mica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Sgaravatti
authors.forename: Rafael B
authors.initials: RB
authors.lastname: Rosa
authors.forename: Patrícia F
authors.initials: PF
authors.lastname: Schuck
authors.forename: César A J
authors.initials: CA
authors.lastname: Ribeiro
authors.forename: Clóvis M D
authors.initials: CM
authors.lastname: Wannmacher
authors.forename: Angela T S
authors.initials: AT
authors.lastname: Wyse
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Dutra-Filho
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D045782:Hemiterpenes; D006801:Humans; D007651:Keto Acids / Q000494:pharmacology*; D007773:Lactates / Q000378:metabolism; D008375:Maple Syrup Urine Disease / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013384:Succinate Cytochrome c Oxidoreductase / Q000378:metabolism
chemical_list: D045782:Hemiterpenes; D007651:Keto Acids; D007773:Lactates; D002245:Carbon Dioxide; C016211:alpha-keto-beta-methylvaleric acid; C001505:alpha-ketoisovalerate; C013082:alpha-ketoisocaproic acid; D013384:Succinate Cytochrome c Oxidoreductase; D005947:Glucose