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Acute Mitochondrial Actions of Glitazones on the Liver: a Crucial Parameter for their Antidiabetic PropertiesSanz M.-N.1 · Sánchez-Martín C.1 · Detaille D.2 · Vial G.2 · Rigoulet M.3 · El-Mir M.-Y.1 · Rodríguez-Villanueva G.1
1Department of Physiology and Pharmacology, University of Salamanca, Salamanca,2INSERM U1055, Fundamental and Applied Bioenergetics, University Joseph Fourier of Grenoble, Grenoble3Université Bordeaux 2, Bordeaux Corresponding Author
María-Nieves Sanz, PhD
Department of Physiology and Pharmacology, University of Salamanca,
Campus Miguel de Unamuno, Edificio Departamental S-12,
Avda. Campo Charro s/n, Salamanca 37007 (Spain)
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Background/aims: Glitazones are synthetic insulin-sensitizing drugs which act as agonists of peroxisome proliferator-activated receptor gamma (PPARγ). However, TZDs action does not exclude independent PPARγ-activation effects. Remarkably, direct mitochondrial action of these agents has not been fully studied yet. Methods: Oxygen consumption rates (JO2) were measured using a Clark-type oxygen electrode in intact hepatocytes and isolated liver mitochondria. Mitochondrial reactive oxygen species (ROS) production was quantified by fluorescence assay. Moreover, activities of mitochondrial respiratory chain complex I, II and III were spectrometrically determined. Results: Pioglitazone and rosiglitazone inhibited JO2 in liver cells and mitochondria. This inhibition affected the state 3 of respiration (in the presence of ADP) and the uncoupled state (after addition of dinitrophenol). Moreover, these agents dramatically reduced mitochondrial ROS production in all situations tested. We also demonstrated that both glitazones specifically inhibited the activities of complex I and complex III, by 50% and 35% respectively. Additionally, they do not modify neither the oxidative phosphorylation yield nor the permeability transition pore opening. Conclusions: Pioglitazone and rosiglitazone reduce both respiration intensity and ROS production, acutely and by a probable PPARγ-independent way, through inhibition of complex I and III activities. This new finding could positively contribute to their anti-diabetic properties.
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