title: Phytanic acid disturbs mitochondrial homeostasis in heart of young rats: a possible pathomechanism of cardiomyopathy in Refsum disease.
abstract: Phytanic acid (Phyt) accumulates in tissues and biological fluids of patients affected by Refsum disease. Although cardiomyopathy is an important clinical manifestation of this disorder, the mechanisms of heart damage are poorly known. In the present study, we investigated the in vitro effects of Phyt on important parameters of oxidative stress in heart of young rats. Phyt significantly increased thiobarbituric acid-reactive substances levels (P < 0.001) and carbonyl formation (P < 0.01), indicating that this fatty acid induces lipid and protein oxidative damage, respectively. In contrast, Phyt did not alter sulfhydryl oxidation. Phyt also decreased glutathione (GSH) concentrations (P < 0.05), an important non-enzymatic antioxidant defense. Moreover, Phyt increased 2',7'-dichlorofluorescin oxidation (DCFH) (P < 0.01), reflecting increased reactive species generation. We also found that the induced lipid and protein oxidative damage, as well as the decreased GSH levels and increased DCFH oxidation provoked by this fatty acid were prevented or attenuated by the reactive oxygen species scavengers melatonin, trolox, and GSH, but not by the nitric oxide inhibitor N: (ω)-nitro-L: -arginine methyl ester, suggesting that reactive oxygen species were involved in these effects. Next, we verified that Phyt strongly inhibited NADH-cytochrome c oxidoreductase (complex I-III) activity (P < 0.001) in heart supernatants, and decreased membrane potential and the NAD(P)H pool in heart mitochondria, indicating that Phyt acts as a metabolic inhibitor and as an uncoupler of the electron transport chain. Therefore, it can be presumed that disturbance of cellular energy and redox homeostasis induced by Phyt may possibly contribute to the cardiomyopathy found in patients affected by Refsum disease.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos N° 2600-Anexo, Porto Alegre, RS, CEP 90035-003, Brazil.
authors.forename: Mateus
authors.initials: M
authors.lastname: Grings
authors.forename: Anelise Miotti
authors.initials: AM
authors.lastname: Tonin
authors.forename: Lisiane Aurélio
authors.initials: LA
authors.lastname: Knebel
authors.forename: Angela
authors.initials: A
authors.lastname: Zanatta
authors.forename: Alana Pimentel
authors.initials: AP
authors.lastname: Moura
authors.forename: Carlos Severo Dutra
authors.initials: CS
authors.lastname: Filho
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D009202:Cardiomyopathies / Q000378:metabolism*; D002839:Chromans / Q000494:pharmacology; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005978:Glutathione / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009249:NADP / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010831:Phytanic Acid / Q000494:pharmacology*; D050050:Protein Carbonylation; D051381:Rats; D017208:Rats, Wistar; D012035:Refsum Disease / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002839:Chromans; D045222:Electron Transport Chain Complex Proteins; D017392:Thiobarbituric Acid Reactive Substances; D010831:Phytanic Acid; D009249:NADP; D019001:Nitric Oxide Synthase; D005978:Glutathione; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D019331:NG-Nitroarginine Methyl Ester