Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 11, Pages 7136-7142Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M513198200
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Phytanic acid (Phyt) increase is associated with the hereditary neurodegenerative Refsum disease. To elucidate the still unclear toxicity of Phyt, mitochondria from brain and heart of adult rats were exposed to free Phyt. Phyt at low micromolar concentrations (maximally: 100 nmol/mg of protein) enhances superoxide (O-2(radical anion))(2) generation. Phyt induces O-2(radical anion) in state 3 ( phosphorylating), as well as in state 4 ( resting). Phyt stimulates O-2(radical anion) generation when the respiratory chain is fed with electrons derived from oxidation of glutamate/ malate, pyruvate/ malate, or succinate in the presence of rotenone. With succinate alone, Phyt suppresses O-2(radical anion) generation caused by reverse electron transport from succinate to complex I. The enhanced O-2(radical anion) generation by Phyt in state 4 is in contrast to the mild uncoupling concept. In this concept uncoupling by nonesterified fatty acids should abolish O-2(radical anion) generation. Stimulation of O-2(radical anion) generation by Phyt is paralleled by inhibition of the electron transport within the respiratory chain or electron leakage from the respiratory chain. The interference of Phyt with the electron transport was demonstrated by inhibition of state 3- and p-trifluoromethoxyphenylhydrazone (FCCP)-dependent respiration, inactivation of the NADH-ubiquinone oxidoreductase complex in permeabilized mitochondria, decrease in reduction of the synthetic electron acceptor 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in state 4, and increase of the mitochondrial NAD(P) H level in FCCP-uncoupled mitochondria. Thus, we suggest that complex I is the main site of Phyt-stimulated O-2(radical anion) generation. Furthermore, inactivation of aconitase and oxidation of the mitochondrial glutathione pool show that enhanced O-2(radical anion) generation with chronic exposure to Phyt causes oxidative damage.
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