title: Evidence that the major metabolites accumulating in medium-chain acyl-CoA dehydrogenase deficiency disturb mitochondrial energy homeostasis in rat brain.
abstract: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an inherited metabolic disorder of fatty acid oxidation in which the affected patients predominantly present high levels of octanoic (OA) and decanoic (DA) acids and their glycine and carnitine by-products in tissues and body fluids. It is clinically characterized by episodic encephalopathic crises with coma and seizures, as well as by progressive neurological involvement, whose pathophysiology is poorly known. In the present work, we investigated the in vitro effects of OA and DA on various parameters of energy homeostasis in mitochondrial preparations from brain of young rats. We found that OA and DA markedly increased state 4 respiration and diminished state 3 respiration as well as the respiratory control ratio, the mitochondrial membrane potential and the matrix NAD(P)H levels. In addition, DA-elicited increase in oxygen consumption in state 4 respiration was partially prevented by atractyloside, indicating the involvement of the adenine nucleotide translocator. OA and DA also reduced ADP/O ratio, CCCP-stimulated respiration and the activities of respiratory chain complexes. The data indicate that the major accumulating fatty acids in MCADD act as uncouplers of oxidative phosphorylation and as metabolic inhibitors. Furthermore, DA, but not OA, provoked a marked mitochondrial swelling and cytochrome c release from mitochondria, reflecting a permeabilization of the inner mitochondrial membrane. Taken together, these data suggest that OA and DA impair brain mitochondrial energy homeostasis that could underlie at least in part the neuropathology of MCADD.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Patrícia Fernanda
authors.initials: PF
authors.lastname: Schuck
authors.forename: Gustavo da Costa
authors.initials: Gda C
authors.lastname: Ferreira
authors.forename: Anelise Miotti
authors.initials: AM
authors.lastname: Tonin
authors.forename: Carolina Maso
authors.initials: CM
authors.lastname: Viegas
authors.forename: Estela Natacha Brandt
authors.initials: EN
authors.lastname: Busanello
authors.forename: Alana Pimentel
authors.initials: AP
authors.lastname: Moura
authors.forename: Angela
authors.initials: A
authors.lastname: Zanatta
authors.forename: Fábio
authors.initials: F
authors.lastname: Klamt
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency*; D000818:Animals; D001278:Atractyloside / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002210:Caprylates / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D003652:Decanoic Acids / Q000378:metabolism*; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D000226:Mitochondrial ADP, ATP Translocases / Q000037:antagonists & inhibitors; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D009249:NADP / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002210:Caprylates; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D001278:Atractyloside; C031071:decanoic acid; D009249:NADP; D045304:Cytochromes c; D000226:Mitochondrial ADP, ATP Translocases; D042964:Acyl-CoA Dehydrogenase; C031492:octanoic acid