Key result
Pioglitazone and rosiglitazone acutely reduce mitochondrial respiration and ROS production via ~50% complex I inhibition.
Why the study?
The direct mitochondrial actions of glitazones have not been fully studied despite their known insulin-sensitizing effects and PPARγ agonism.
Pioglitazone and rosiglitazone acutely reduce respiration intensity and ROS production in liver mitochondria through inhibition of complex I and III, potentially contributing to their antidiabetic properties.
Direct mitochondrial effects of TZDs in hepatocytes require in vivo validation; leaves open contribution to clinical efficacy or toxicity.
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 (JO(2)) 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 JO(2) 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.
No takes yet. Share an insight, caveat, or question.
Sanz et al. (2011) studied this question. Pioglitazone and rosiglitazone was evaluated on Activities of mitochondrial respiratory chain complex I and III (50% and 35% inhibition respectively). Pioglitazone and rosiglitazone acutely reduced respiration intensity and ROS production through specific inhibition of mitochondrial complex I (by 50%) and complex III (by 35%) activities.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: