title: Deregulation of mitochondrial functions provoked by long-chain fatty acid accumulating in long-chain 3-hydroxyacyl-CoA dehydrogenase and mitochondrial permeability transition deficiencies in rat heart--mitochondrial permeability transition pore opening as a potential contributing pathomechanism of cardiac alterations in these disorders.
abstract: Mitochondrial trifunctional protein and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiencies are fatty acid oxidation disorders biochemically characterized by tissue accumulation of long-chain fatty acids and derivatives, including the monocarboxylic long-chain 3-hydroxy fatty acids (LCHFAs) 3-hydroxytetradecanoic acid (3HTA) and 3-hydroxypalmitic acid (3HPA). Patients commonly present severe cardiomyopathy for which the pathogenesis is still poorly established. We investigated the effects of 3HTA and 3HPA, the major metabolites accumulating in these disorders, on important parameters of mitochondrial homeostasis in Ca(2+) -loaded heart mitochondria. 3HTA and 3HPA significantly decreased mitochondrial membrane potential, the matrix NAD(P)H pool and Ca(2+) retention capacity, and also induced mitochondrial swelling. These fatty acids also provoked a marked decrease of ATP production reflecting severe energy dysfunction. Furthermore, 3HTA-induced mitochondrial alterations were completely prevented by the classical mitochondrial permeability transition (mPT) inhibitors cyclosporin A and ADP, as well as by ruthenium red, a Ca(2+) uptake blocker, indicating that LCHFAs induced Ca(2+)-dependent mPT pore opening. Milder effects only achieved at higher doses of LCHFAs were observed in brain mitochondria, implying a higher vulnerability of heart to these fatty acids. By contrast, 3HTA and docosanoic acids did not change mitochondrial homeostasis, indicating selective effects for monocarboxylic LCHFAs. The present data indicate that the major LCHFAs accumulating in mitochondrial trifunctional protein and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiencies induce mPT pore opening, compromising Ca(2+) homeostasis and oxidative phosphorylation more intensely in the heart. It is proposed that these pathomechanisms may contribute at least in part to the severe cardiac alterations characteristic of patients affected by these diseases.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Cristiane
authors.initials: C
authors.lastname: Cecatto
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Fernanda H
authors.initials: FH
authors.lastname: Hickmann
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Marília D N
authors.initials: MD
authors.lastname: Rodrigues
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Alexandre U
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, Brazil.|Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Brazil.
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D009202:Cardiomyopathies / Q000201:enzymology / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000201:enzymology / Q000378:metabolism; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase / Q000172:deficiency / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D017240:Mitochondrial Myopathies / Q000201:enzymology / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects; D063991:Mitochondrial Trifunctional Protein / Q000172:deficiency / Q000378:metabolism; D009227:Myristic Acids / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D009422:Nervous System Diseases / Q000201:enzymology / Q000378:metabolism; D009928:Organ Specificity; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010169:Palmitic Acids / Q000378:metabolism*; D017208:Rats, Wistar; D012206:Rhabdomyolysis / Q000201:enzymology / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009227:Myristic Acids; D010169:Palmitic Acids; C009893:beta-hydroxymyristic acid; C108229:3-hydroxypalmitic acid; D009249:NADP; D000255:Adenosine Triphosphate; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D063991:Mitochondrial Trifunctional Protein
keywords: calcium homeostasis; heart; long-chain 3-hydroxy fatty acid; mitochondrial bioenergetics; mitochondrial permeability transition