title: 3-Methylcrotonylglycine disrupts mitochondrial energy homeostasis and inhibits synaptic Na(+),K (+)-ATPase activity in brain of young rats.
abstract: Deficiency of 3-methylcrotonyl-CoA carboxylase activity is an inherited metabolic disease biochemically characterized by accumulation and high urinary excretion of 3-methylcrotonylglycine (3MCG), and also of 3-hydroisovalerate in lesser amounts. Affected patients usually have neurologic dysfunction, brain abnormalities and cardiomyopathy, whose pathogenesis is still unknown. The present study investigated the in vitro effects of 3MCG on important parameters of energy metabolism, including CO(2) production from labeled acetate, enzyme activities of the citric acid cycle, as well as of the respiratory chain complexes I-IV (oxidative phosphorylation), creatine kinase (intracellular ATP transfer), and synaptic Na(+),K(+)-ATPase (neurotransmission) in brain cortex of young rats. 3MCG significantly reduced CO(2) production, implying that this compound compromises citric acid cycle activity. Furthermore, 3MCG diminished the activities of complex II-III of the respiratory chain, mitochondrial creatine kinase and synaptic membrane Na(+),K(+)-ATPase. Furthermore, antioxidants were able to attenuate or fully prevent the inhibitory effect of 3MCG on creatine kinase and synaptic membrane Na(+),K(+)-ATPase activities. We also observed that lipid peroxidation was elicited by 3MCG, suggesting the involvement of free radicals on 3MCG-induced effects. Considering the importance of the citric acid cycle and the electron flow through the respiratory chain for brain energy production, creatine kinase for intracellular energy transfer, and Na(+),K(+)-ATPase for the maintenance of the cell membrane potential, the present data indicate that 3MCG potentially impairs mitochondrial brain energy homeostasis and neurotransmission. It is presumed that these pathomechanisms may be involved in the neurological damage found in patients affected by 3-methylcrotonyl-CoA carboxylase deficiency.
authors: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Anexo, Porto Alegre, RS 90035-003, Brazil.
authors: Alana Pimentel
authors: AP
authors: Moura
authors: César Augusto João
authors: CA
authors: Ribeiro
authors: Ângela
authors: Â
authors: Zanatta
authors: Estela Natacha Brandt
authors: EN
authors: Busanello
authors: Anelise Miotti
authors: AM
authors: Tonin
authors: Moacir
authors: M
authors: Wajner
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D002245:Carbon Dioxide / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D003402:Creatine Kinase / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000201:enzymology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000975:Antioxidants; D045222:Electron Transport Chain Complex Proteins; D017392:Thiobarbituric Acid Reactive Substances; D002245:Carbon Dioxide; C002163:beta-methylcrotonylglycine; D003402:Creatine Kinase; D000254:Sodium-Potassium-Exchanging ATPase; D005998:Glycine