title: Inhibition of cytochrome c oxidase activity in rat cerebral cortex and human skeletal muscle by D-2-hydroxyglutaric acid in vitro.
abstract: L-2-Hydroxyglutaric (LGA) and D-2-hydroxyglutaric (DGA) acids are the characteristic metabolites accumulating in the neurometabolic disorders known as L-2-hydroxyglutaric aciduria and D-2-hydroxyglutaric aciduria, respectively. Although these disorders are predominantly characterized by severe neurological symptoms, the neurotoxic mechanisms of brain damage are virtually unknown. In this study we have evaluated the role of LGA and DGA at concentrations ranging from 0.01 to 5.0 mM on various parameters of energy metabolism in cerebral cortex slices and homogenates of 30-day-old Wistar rats, namely glucose uptake, CO(2) production and the respiratory chain enzyme activities of complexes I to IV. DGA significantly decreased glucose utilization (2.5 and 5.0 mM) by brain homogenates and CO(2) production (5 mM) by brain homogenates and slices, whereas LGA had no effect on either measurement. Furthermore, DGA significantly inhibited cytochrome c oxidase activity (complex IV) (EC 1.9.3.1) in a dose-dependent manner (35-95%) at doses as low as 0.5 mM, without compromising the other respiratory chain enzyme activities. In contrast, LGA did not interfere with these activities. Our results suggest that the strong inhibition of cytochrome c oxidase activity by increased levels of DGA could be related to the neurodegeneration of patients affected by D-2-hydroxyglutaric aciduria.
authors.affiliation: Department of Biochemistry, Institute of Basic Sciences and Health, UFRGS, Porto Alegre, RS, Brazil.
authors.forename: Cleide G
authors.initials: CG
authors.lastname: da Silva
authors.forename: César A J
authors.initials: CA
authors.lastname: Ribeiro
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Dutra-Filho
authors.forename: Angela T S
authors.initials: AT
authors.lastname: Wyse AT
authors.forename: Clóvis M D
authors.initials: CM
authors.lastname: Wannmacher
authors.forename: João J F
authors.initials: JJ
authors.lastname: Sarkis
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D005977:Glutarates / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D013237:Stereoisomerism
chemical_list: D005977:Glutarates; D002245:Carbon Dioxide; C019417:alpha-hydroxyglutarate; D003576:Electron Transport Complex IV; D014450:Electron Transport Complex III; D005947:Glucose