COPPER AND IRON TOXICITY IN A MODEL OF RAT LIVER ISOLATED MITOCHONDRIA: OXIDATIVE STRESS, ANTIOXIDANT PROTECTION AND REDOX HOMEOSTASIS

ACOSTA, JM; REYNOSO, S; SAPORITO MAGRIÑÁ, C.; PAREDES FLEITAS, P; REPETTO, M; MUSACCO SEBIO, R; BAJICOFF, S; BOVERIS, A

Mar del Plata, Buenos Aires

Congreso; LXI Reunión anual de la Sociedad Argentina de Investigación Clínica; 2016

Sociedad Argentina de Investigación Clínica

Introduction: The transition metals copper (Cu) and iron (Cu) are necessary at low concentration for different vital functions whereas at higher concentrations they become toxic. Wilson?s disease and Haemochromatosis are examples of Cu and Fe toxicity. Here, the pathophysiology proposed in both cases involves the ability of the metals to produce hydroxyl radical (OH?) through the Fenton/Haber-Weiss reaction. Hypothesis: Cu and Fe are able to produce oxidative damage by OH? formation as well as direct action of the metals on biomolecules. Methodology: Rat liver isolated mitochondria were exposed to Cu and Fe overloads. Mitochondrial function (oxygen consumption assessed in a Clark-type electrode), phospholipid peroxidation (TBARS) and total thiol content (reaction with DTNB) were determined. Results: Both metals are able to decrease the mitochondrial function, much lower concentrations were needed for Cu to become toxic. The decrease of the oxygen consumption and respiratory control was considerably more pronounced when mitochondria were exposed to conditions of high H2O2/O2- production, showing the participation of these species in metal toxicity. Both metals induced phospholipid peroxidation in a concentration-dependent manner but, interestingly, only when substrates for oxygen consumption were available. Regarding Cu, the antioxidant glutathione (GSH) was the most efficient in preventing mitochondrial dysfunction and phospholipid oxidation. Regarding Fe, these protective effects were only observed upon butylated hydroxytoluene (BHT) supplementation. Cu, but not Fe, is able to react in a direct and stoichiometric way with the mitochondrial thiol groups. Conclusion: Cu and Fe toxicity present at some point a common toxic mechanism of OH? generation through Fenton reaction. However, Cu may also participate in intracellular oxidative mechanism by direct reaction with protein thiol groups and, specially, GSH.