Long-chain 3-hydroxy fatty acids accumulating in long-chain 3-hydroxyacyl-CoA dehydrogenase and mitochondrial trifunctional protein deficiencies uncouple oxidative phosphorylation in heart mitochondria.
Cardiomyopathy is a common clinical feature of some inherited disorders of mitochondrial fatty acid β-oxidation including mitochondrial trifunctional protein (MTP) and isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiencies. Since individuals affected by these disorders present tissue accumulation of various fatty acids, including long-chain 3-hydroxy fatty acids, in the present study we investigated the effect of 3-hydroxydecanoic (3 HDCA), 3-hydroxydodecanoic (3 HDDA), 3-hydroxytetradecanoic (3 HTA) and 3-hydroxypalmitic (3 HPA) acids on mitochondrial oxidative metabolism, estimated by oximetry, NAD(P)H content, hydrogen peroxide production, membrane potential (ΔΨ) and swelling in rat heart mitochondrial preparations. We observed that 3 HTA and 3 HPA increased resting respiration and diminished the respiratory control and ADP/O ratios using glutamate/malate or succinate as substrates. Furthermore, 3 HDDA, 3 HTA and 3 HPA decreased ΔΨ, the matrix NAD(P)H pool and hydrogen peroxide production. These data indicate that these fatty acids behave as uncouplers of oxidative phosphorylation. We also verified that 3 HTA-induced uncoupling-effect was not mediated by the adenine nucleotide translocator and that this fatty acid induced the mitochondrial permeability transition pore opening in calcium-loaded organelles since cyclosporin A prevented the reduction of mitochondrial ΔΨ and swelling provoked by 3 HTA. The present data indicate that major 3-hydroxylated fatty acids accumulating in MTP and LCHAD deficiencies behave as strong uncouplers of oxidative phosphorylation potentially impairing heart energy homeostasis.
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003 Porto Alegre, RS, Brazil.
Anelise M
AM
Tonin
Alexandre U
AU
Amaral
Estela N B
EN
Busanello
Mateus
M
Grings
Roger F
RF
Castilho
Moacir
M
Wajner
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism*; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D008929:Mitochondria, Heart / Q000378:metabolism*; D017240:Mitochondrial Myopathies; D024101:Mitochondrial Proteins / Q000378:metabolism*; D063991:Mitochondrial Trifunctional Protein / Q000172:deficiency; D009124:Muscle Proteins / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009422:Nervous System Diseases; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D010523:Peripheral Nervous System Diseases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012174:Retinitis Pigmentosa / Q000378:metabolism*; D012206:Rhabdomyolysis
D005227:Fatty Acids; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D006861:Hydrogen Peroxide; D015094:3-Hydroxyacyl CoA Dehydrogenases; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D063991:Mitochondrial Trifunctional Protein