BACKGROUND: Dietary copper overload in the rat is associated with morphological abnormalities and lipid peroxidation of hepatic mitochondria. This study was designed to determine if copper hepatotoxicity was associated with functional alterations in mitochondrial respiration in conjunction with lipid peroxidation. METHODS: Weanling male rats were pair-fed for 8 weeks on diets containing normal or high levels of copper in combination with sufficient vitamin E. Serum and liver samples were obtained, and hepatic mitochondria were isolated by differential centrifugation. RESULTS: Oxidant injury (decreased levels of hepatic glutathione and alpha tocopherol and increased levels of mitochondrial thiobarbituric acid-reacting substances) was present in the copper-overloaded rats. Serum aminotransferase levels correlated with concentrations of mitochondrial copper and thiobarbituric acid-reacting substances. Copper overload caused a decrease in state 3 respiration and the respiratory control ratio in hepatic mitochondria when several electron donors were used. Analysis of the oxidoreductase activities of the four mitochondrial electron transport protein complexes showed that complex IV (cytochrome C oxidase) activity was reduced by 60% in copper overload. CONCLUSIONS: Functional abnormalities of mitochondria accompany lipid peroxidation and the morphological alterations caused by copper overload, supporting the hypothesis that the mitochondrion is one of the major intracellular targets in copper hepatotoxicity.
BACKGROUND: Dietary copper overload in the rat is associated with morphological abnormalities and lipid peroxidation of hepatic mitochondria. This study was designed to determine if copper hepatotoxicity was associated with functional alterations in mitochondrial respiration in conjunction with lipid peroxidation. METHODS: Weanling male rats were pair-fed for 8 weeks on diets containing normal or high levels of copper in combination with sufficient vitamin E. Serum and liver samples were obtained, and hepatic mitochondria were isolated by differential centrifugation. RESULTS:Oxidant injury (decreased levels of hepatic glutathione and alpha tocopherol and increased levels of mitochondrial thiobarbituric acid-reacting substances) was present in the copper-overloaded rats. Serum aminotransferase levels correlated with concentrations of mitochondrial copper and thiobarbituric acid-reacting substances. Copper overload caused a decrease in state 3 respiration and the respiratory control ratio in hepatic mitochondria when several electron donors were used. Analysis of the oxidoreductase activities of the four mitochondrial electron transport protein complexes showed that complex IV (cytochrome C oxidase) activity was reduced by 60% in copper overload. CONCLUSIONS: Functional abnormalities of mitochondria accompany lipid peroxidation and the morphological alterations caused by copper overload, supporting the hypothesis that the mitochondrion is one of the major intracellular targets in copper hepatotoxicity.
Authors: Hans Zischka; Josef Lichtmannegger; Sabine Schmitt; Nora Jägemann; Sabine Schulz; Daniela Wartini; Luise Jennen; Christian Rust; Nathanael Larochette; Lorenzo Galluzzi; Veronique Chajes; Nathan Bandow; Valérie S Gilles; Alan A DiSpirito; Irene Esposito; Martin Goettlicher; Karl H Summer; Guido Kroemer Journal: J Clin Invest Date: 2011-04 Impact factor: 14.808
Authors: Fabien Pierron; Vincent Bourret; Jérôme St-Cyr; Peter G C Campbell; Louis Bernatchez; Patrice Couture Journal: Ecotoxicology Date: 2009-04-29 Impact factor: 2.823
Authors: Valentina Medici; Gaurav V Sarode; Eleonora Napoli; Gyu-Young Song; Noreene M Shibata; Andre O Guimarães; Charles E Mordaunt; Dorothy A Kieffer; Tagreed A Mazi; Anna Czlonkowska; Tomasz Litwin; Janine M LaSalle; Cecilia Giulivi Journal: Liver Int Date: 2020-09-30 Impact factor: 5.828