title: Mitochondrial bioenergetics deregulation caused by long-chain 3-hydroxy fatty acids accumulating in LCHAD and MTP deficiencies in rat brain: a possible role of mPTP opening as a pathomechanism in these disorders?
abstract: Long-chain 3-hydroxylated fatty acids (LCHFA) accumulate in long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiencies. Affected patients usually present severe neonatal symptoms involving cardiac and hepatic functions, although long-term neurological abnormalities are also commonly observed. Since the underlying mechanisms of brain damage are practically unknown and have not been properly investigated, we studied the effects of LCHFA on important parameters of mitochondrial homeostasis in isolated mitochondria from cerebral cortex of developing rats. 3-Hydroxytetradecanoic acid (3 HTA) reduced mitochondrial membrane potential, NAD(P)H levels, Ca(2+) retention capacity and ATP content, besides inducing swelling, cytochrome c release and H2O2 production in Ca(2+)-loaded mitochondrial preparations. We also found that cyclosporine A plus ADP, as well as ruthenium red, a Ca(2+) uptake blocker, prevented these effects, suggesting the involvement of the mitochondrial permeability transition pore (mPTP) and an important role for Ca(2+), respectively. 3-Hydroxydodecanoic and 3-hydroxypalmitic acids, that also accumulate in LCHAD and MTP deficiencies, similarly induced mitochondrial swelling and decreased ATP content, but to a variable degree pending on the size of their carbon chain. It is proposed that mPTP opening induced by LCHFA disrupts brain bioenergetics and may contribute at least partly to explain the neurologic dysfunction observed in patients affected by LCHAD and MTP deficiencies.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Research Unit for Molecular Medicine, Aarhus University Hospital, Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark.
authors.forename: Anelise Miotti
authors.initials: AM
authors.lastname: Tonin
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Alexandre Umpierrez
authors.initials: AU
authors.lastname: Amaral
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Estela Natacha
authors.initials: EN
authors.lastname: Busanello
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Juciano
authors.initials: J
authors.lastname: Gasparotto
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Gelain
authors.affiliation: Research Unit for Molecular Medicine, Aarhus University Hospital, Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Gregersen
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, RS, Brazil. Electronic address: mwajner@ufrgs.br.
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000172:deficiency* / Q000378:metabolism; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D006706:Homeostasis; D006861:Hydrogen Peroxide / Q000378:metabolism; D007850:Lauric Acids / Q000494:pharmacology*; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D017240:Mitochondrial Myopathies / Q000378:metabolism* / Q000473:pathology; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects; D063991:Mitochondrial Trifunctional Protein / Q000378:metabolism* / Q000172:deficiency; D009227:Myristic Acids / Q000494:pharmacology*; D009249:NADP / Q000378:metabolism; D009422:Nervous System Diseases / Q000378:metabolism* / Q000473:pathology; D016877:Oxidants / Q000378:metabolism; D010169:Palmitic Acids / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012206:Rhabdomyolysis / Q000378:metabolism* / Q000473:pathology
chemical_list: D007850:Lauric Acids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009227:Myristic Acids; D016877:Oxidants; D010169:Palmitic Acids; C022145:3-hydroxydodecanoic acid; C009893:beta-hydroxymyristic acid; C108229:3-hydroxypalmitic acid; D009249:NADP; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D015094:3-Hydroxyacyl CoA Dehydrogenases; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D063991:Mitochondrial Trifunctional Protein; D002118:Calcium
keywords: Brain energy homeostasis; Calcium; Long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency; Mitochondrial trifunctional protein deficiency; Permeability transition pore