Journal
LIFE SCIENCES
Volume 92, Issue 23, Pages 1110-1117Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2013.04.009
Keywords
Mitochondria; Organic hydroperoxide; Oxidative damage; Melatonin; Redox-balance
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Aims: The present study was designed for further evaluation of the biochemical mechanism of hepatic mitochondrialdysfunction under oxidative damages induced by organic hydroperoxide, tert-butyl hydroperoxide (tBHP), for estimation of the molecular targets impaired during oxidative stress, and for investigation of the role of Ca2+ ions in mitochondrial oxidative reactions and of the protective effect of melatonin during mitochondrial peroxidative damage. Main methods: Mitochondria were isolated by differential centrifugation from the rat liver. The effects of tBHP exposure, EDTA, Ca2+ ions and melatonin on mitochondrial respiratory activity, mitochondrial enzyme activities and redox status were measured. Key findings: The present study provides evidence that tBHP (at low concentrations of 0.02-0.065 mM, in EDTA-free medium) induced uncoupling of the oxidation and phosphorylation processes and decreased the efficiency of the phosphorylation reaction. This effect depended on the respiratory substrate used. The presence of EDTA prevented oxidative impairment of mitochondrial respiration, but Ca2+ ions in the medium enhanced oxidant-induced mitochondrial damage considerably. In the presence of 0.5 mM EDTA, tBHP (at high concentrations, 0.5-2 mM) considerably oxidized mitochondrial reduced glutathione, enhanced accumulation of membrane lipid peroxidation products and mixed protein-glutathione disulfides and led to an inhibition of oxoglutarate dehydrogenase and succinate dehydrogenase. Significance: Direct oxidative modification of enzymatic complexes of the respiratory chain and mitochondrial matrix, mitochondrial reduced glutathione depletion, protein glutathionylation, membrane lipid peroxidation and Ca2+ overload are the main events of mitochondrial peroxidative damages. Experiments in vitro demonstrated that melatonin inhibited the mitochondrial peroxidative damage, preventing redox-balance changes and succinate dehydrogenase inactivation. (C) 2013 Elsevier Inc. All rights reserved.
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