title: The effect of valinomycin in fibroblasts from patients with fatty acid oxidation disorders.
abstract: Disorders of the carnitine cycle and of the beta oxidation spiral impair the ability to obtain energy from fats at time of fasting and stress. This can result in hypoketotic hypoglycemia, cardiomyopathy, cardiac arrhythmia and other chronic medical problems. The in vitro study of fibroblasts from patients with these conditions is impaired by their limited oxidative capacity. Here we evaluate the capacity of valinomycin, a potassium ionophore that increases mitochondrial respiration, to increase the oxidation of fatty acids in cells from patients with inherited fatty acid oxidation defects. The addition of valinomycin to fibroblasts decreased the accumulation of the lipophilic cation tetraphenylphosphonium (TPP(+)) at low concentrations due to the dissipation of the mitochondrial membrane potential. At higher doses, valinomycin increased TPP(+) accumulation due to the increased potassium permeability of the plasma membrane and subsequent cellular hyperpolarization. The incubation of normal fibroblasts with valinomycin increased [(14)C]-palmitate oxidation (measured as [(14)C]O2 release) in a dose-dependent manner. By contrast, valinomycin failed to increase palmitate oxidation in fibroblasts from patients with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This was not observed in fibroblasts from patients heterozygous for this condition. These results indicate that valinomycin can increase fatty acid oxidation in normal fibroblasts and could be useful to differentiate heterozygotes from patients affected with VLCAD deficiency.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, 84132, USA.
authors.forename: Uzochi Chimdinma
authors.initials: UC
authors.lastname: Ndukwe Erlingsson
authors.forename: Francesco
authors.initials: F
authors.lastname: Iacobazzi
authors.forename: Aiping
authors.initials: A
authors.lastname: Liu
authors.forename: Orly
authors.initials: O
authors.lastname: Ardon
authors.forename: Marzia
authors.initials: M
authors.lastname: Pasquali
authors.forename: Nicola
authors.initials: N
authors.lastname: Longo
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002331:Carnitine / Q000737:chemistry; D002478:Cells, Cultured; D000080984:Congenital Bone Marrow Failure Syndromes; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000378:metabolism*; D009135:Muscular Diseases / Q000378:metabolism*; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D014634:Valinomycin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D005227:Fatty Acids; D014634:Valinomycin; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002331:Carnitine; D010100:Oxygen
keywords: Carnitine; Fatty acid oxidation; Valinomycin; Very long chain acyl CoA dehydrogenase deficiency