title: Acute mitochondrial actions of glitazones on the liver: a crucial parameter for their antidiabetic properties.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain. nievesanz@usal.es
authors.forename: María-Nieves
authors.initials: MN
authors.lastname: Sanz
authors.forename: Carlos
authors.initials: C
authors.lastname: Sánchez-Martín
authors.forename: Dominique
authors.initials: D
authors.lastname: Detaille
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vial
authors.forename: Michel
authors.initials: M
authors.lastname: Rigoulet
authors.forename: Mohammed-Yehia
authors.initials: MY
authors.lastname: El-Mir
authors.forename: Gloria
authors.initials: G
authors.lastname: Rodríguez-Villanueva
mesh_terms: D000818:Animals; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D014450:Electron Transport Complex III / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; C478189:respiratory complex II; D000077154:Rosiglitazone; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D000077205:Pioglitazone