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Vol. 28, No. 5, 2011
Issue release date: 2011
Cell Physiol Biochem 2011;28:899–910
(DOI:10.1159/000335804)

Acute Mitochondrial Actions of Glitazones on the Liver: a Crucial Parameter for their Antidiabetic Properties

Sanz 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
email Corresponding Author

Abstract

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.


 Outline


 goto top of outline Key Words

  • Liver
  • Mitochondria
  • Glitazones
  • Direct effects
  • Oxygen consumption
  • Oxidative phosphorylation
  • ROS production
  • Electron transport chain complexes
  • PTP

 goto top of outline Abstract

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.

Copyright © 2011 S. Karger AG, Basel


 goto top of outline Author Contacts

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)
E-Mail nievesanz@usal.es or E-Mail nieves.sanz@inserm.fr


 goto top of outline Article Information

Accepted: October 14, 2011
Published online: December 15, 2011
Number of Print Pages : 12


 goto top of outline Publication Details

Cellular Physiology and Biochemistry (International Journal of Experimental Cellular Physiology, Biochemistry andPharmacology)

Vol. 28, No. 5, Year 2011 (Cover Date: 2011)

Journal Editor: F. Lang, Tübingen
ISSN: 1015–8987 (Print), eISSN: 1421–9778 (Online)

For additional information: http://www.karger.com/journals/cpb


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

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.



 goto top of outline Author Contacts

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)
E-Mail nievesanz@usal.es or E-Mail nieves.sanz@inserm.fr


 goto top of outline Article Information

Accepted: October 14, 2011
Published online: December 15, 2011
Number of Print Pages : 12


 goto top of outline Publication Details

Cellular Physiology and Biochemistry (International Journal of Experimental Cellular Physiology, Biochemistry andPharmacology)

Vol. 28, No. 5, Year 2011 (Cover Date: 2011)

Journal Editor: F. Lang, Tübingen
ISSN: 1015–8987 (Print), eISSN: 1421–9778 (Online)

For additional information: http://www.karger.com/journals/cpb


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.