title: Disturbance of mitochondrial energy homeostasis caused by the metabolites accumulating in LCHAD and MTP deficiencies in rat brain.
abstract: OBJECTIVE
  We investigated the in vitro effects of 3-hydroxydodecanoic (3HDA), 3-hydroxytetradecanoic (3HTA) and 3-hydroxypalmitic (3HPA) acids, which accumulate in tissues of patients affected by mitochondrial trifunctional protein (MTP) and isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiencies, on various parameters of energy homeostasis in mitochondrial preparations from brain of young rats.
  
  
  METHODS
  We measured the respiratory parameters state 4, state 3, respiratory control ratio (RCR) and ADP/O ratio by the rate of oxygen consumption, as well as the mitochondrial membrane potential and the matrix NAD(P)H levels in the presence of the fatty acids.
  
  
  RESULTS
  We found that 3HDA, 3HTA and 3HPA markedly increased state 4 respiration and diminished the RCR using glutamate plus malate or succinate as substrates. 3HTA and 3HPA also diminished the mitochondrial membrane potential and the matrix NAD(P)H levels. In addition, 3HTA decreased state 3 respiration using glutamate/malate, but not pyruvate/malate or succinate as substrates. Our data indicate that the long-chain 3-hydroxy fatty acids that accumulate in LCHAD/MTP deficiencies act as uncouplers of oxidative phosphorylation, while 3HTA also behaves as a metabolic inhibitor.
  
  
  CONCLUSIONS
  It is presumed that impairment of brain energy homeostasis caused by these endogenous accumulating compounds may contribute at least in part to the neuropathology of LCHAD/MTP deficiencies.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Anelise M
authors.initials: AM
authors.lastname: Tonin
authors.forename: Gustavo C
authors.initials: GC
authors.lastname: Ferreira
authors.forename: Mateus
authors.initials: M
authors.lastname: Grings
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Viegas
authors.forename: Estela N
authors.initials: EN
authors.lastname: Busanello
authors.forename: Alexandre U
authors.initials: AU
authors.lastname: Amaral
authors.forename: Angela
authors.initials: A
authors.lastname: Zanatta
authors.forename: Patrícia Fernanda
authors.initials: PF
authors.lastname: Schuck
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000172:deficiency* / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D006706:Homeostasis / Q000187:drug effects; D007850:Lauric Acids / Q000494:pharmacology*; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D063991:Mitochondrial Trifunctional Protein; D009097:Multienzyme Complexes / Q000172:deficiency* / Q000187:drug effects / Q000378:metabolism; D009227:Myristic Acids / Q000494:pharmacology*; D009249:NADP / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D007850:Lauric Acids; D009097:Multienzyme Complexes; D009227:Myristic Acids; C022145:3-hydroxydodecanoic acid; C009893:beta-hydroxymyristic acid; D009249:NADP; D015094:3-Hydroxyacyl CoA Dehydrogenases; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D063991:Mitochondrial Trifunctional Protein