Journal of Bioenergetics and Biomembranes

, Volume 38, Issue 1, pp 33–42 | Cite as

The ROS Production Induced by a Reverse-Electron Flux at Respiratory-Chain Complex 1 is Hampered by Metformin

  • Cécile Batandier
  • Bruno Guigas
  • Dominique Detaille
  • M. El-Mir
  • Eric Fontaine
  • M. Rigoulet
  • X. M. Leverve
Original Paper

Abstract

Mitochondrial reactive oxygen species (ROS) production was investigated in mitochondria extracted from liver of rats treated with or without metformin, a mild inhibitor of respiratory chain complex 1 used in type 2 diabetes. A high rate of ROS production, fully suppressed by rotenone, was evidenced in non-phosphorylating mitochondria in the presence of succinate as a single complex 2 substrate. This ROS production was substantially lowered by metformin pretreatment and by any decrease in membrane potential (Δ < eqid1 > m), redox potential (NADH/NAD), or phosphate potential, as induced by malonate, 2,4-dinitrophenol, or ATP synthesis, respectively. ROS production in the presence of glutamate–malate plus succinate was lower than in the presence of succinate alone, but higher than in the presence of glutamate–malate. Moreover, while rotenone both increased and decreased ROS production at complex 1 depending on forward (glutamate–malate) or reverse (succinate) electron flux, no ROS overproduction was evidenced in the forward direction with metformin. Therefore, we propose that reverse electron flux through complex 1 is an alternative pathway, which leads to a specific metformin-sensitive ROS production.

Keywords

Metformin ROS Oxidative phosphorylation Rat liver mitochondria Rotenone Malonate Antimycin Membrane potential 

Abbreviations:

ΔΨm

electrical potential difference across the mitochondrial inner membrane

ΔpHm

pH difference across the mitochondrial inner membrane

DNP

2,4-dinitrophenol

JO2

oxygen consumption rate

ROS

reactive oxygen species

FFA–BSA

free fatty acid – bovine serum albumin

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. Anderson, WM, Trgovcich-Zacok, D (1995) Biochim Biophys Acta 1230:186–193.CrossRefPubMedGoogle Scholar
  2. Anonymous (1998) Lancet 352:854–865.Google Scholar
  3. Batandier, C, Leverve, X, Fontaine, E (2004) J Biol Chem 279:17197–17204.CrossRefPubMedGoogle Scholar
  4. Bernardi, P, Petronilli, V, Di Lisa, F, et al (2001) Trends Biochem Sci 26:112–117.CrossRefPubMedGoogle Scholar
  5. Boveris, A, Chance, B (1973) Biochem J 134:707–716.PubMedGoogle Scholar
  6. Brownlee, M (2001) Nature 414:813–820.PubMedCrossRefGoogle Scholar
  7. Chance, B, Hollunger, G (1961a) J Biol Chem 236:1534–1543.Google Scholar
  8. Chance, B, Hollunger, G (1961b) J Biol Chem 236:1562–1568.Google Scholar
  9. Chauvin, C, De Oliveira, F, Ronot, X, et al (2001) J Biol Chem 276:41394–41398.CrossRefPubMedGoogle Scholar
  10. Desagher, S, Martinou, JC (2000) Trends Cell Biol 10:369–377.CrossRefPubMedGoogle Scholar
  11. Detaille, D, Guigas, B, Chauvin, C, et al (2005) Diabetes 54:2179–2187.PubMedCrossRefGoogle Scholar
  12. Droge, W (2002) Physiol Rev 82:47–95.PubMedGoogle Scholar
  13. Du, XL, Edelstein, D, Rossetti, L, et al (2000) Proc Natl Acad Sci U.S.A. 97:12222–12226.CrossRefPubMedGoogle Scholar
  14. Du, X, Matsumura, T, Edelstein, D, et al (2003) J Clin Invest 112:1049–1057.CrossRefPubMedGoogle Scholar
  15. El-Mir, MY, Nogueira, V, Fontaine, E, et al (2000) J Biol Chem 275:223–228.CrossRefPubMedGoogle Scholar
  16. Erecinska, M, Wilson, D F (1982) J Membr Biol 70:1–14.CrossRefPubMedGoogle Scholar
  17. Fontaine, E, Eriksson, O, Ichas, F, et al (1998) J Biol Chem 273:12662–12668.CrossRefPubMedGoogle Scholar
  18. Forman, NG, Wilson, DF (1982) J Biol Chem 257:12908–12915.PubMedGoogle Scholar
  19. Guigas, B, Detaille, D, Chauvin, C, et al (2004) Biochem J 382:877–884.CrossRefPubMedGoogle Scholar
  20. Hill, HD, Straka, JG (1988) Anal Biochem 170:203–208.CrossRefPubMedGoogle Scholar
  21. Hinkle, PC, Butow, RA, Racker, E, et al (1967) J Biol Chem 242:5169–5173.PubMedGoogle Scholar
  22. Kagawa, Y, Cha, SH, Hasegawa, K, et al (1999) Biochem Biophys Res Commun 266:662–676.CrossRefPubMedGoogle Scholar
  23. Klingenberg, M, Slenczka, W (1959) Biochem Z 331:486–517.PubMedGoogle Scholar
  24. Korshunov, SS, Korkina, OV, Ruuge, EK, et al (1998) FEBS Lett 435:215–218.CrossRefPubMedGoogle Scholar
  25. Korshunov, SS, Skulachev, VP, Starkov, AA (1997) FEBS Lett 416:15–18.CrossRefPubMedGoogle Scholar
  26. Kudin, AP, Bimpong-Buta, NY, Vielhaber, S, et al (2004) J Biol Chem 279:4127–4135.CrossRefPubMedGoogle Scholar
  27. Kushnareva, Y, Murphy, AN, Andreyev, A (2002) Biochem J 368:545–553.CrossRefPubMedGoogle Scholar
  28. Kwong, LK, Sohal, RS (1998) Arch Biochem Biophys 350:118–126.CrossRefPubMedGoogle Scholar
  29. Lambert, AJ, Brand, MD (2004a) J Biol Chem 279:39414–39420.CrossRefGoogle Scholar
  30. Lambert, AJ, Brand, MD (2004b) Biochem J 382:511–517.CrossRefGoogle Scholar
  31. Lebuffe, G, Schumacker, PT, Shao, ZH, et al (2003) Am J Physiol Heart Circ Physiol 284:H299–H308.PubMedGoogle Scholar
  32. Lee, HC, Wei, YH (2000) J Biomed Sci 7:2–15.PubMedCrossRefGoogle Scholar
  33. Liu, Y, Fiskum, G, Schubert, D (2002) J Neurochem 80:780–787.CrossRefPubMedGoogle Scholar
  34. Newmeyer, DD, Ferguson-Miller, S (2003) Cell 112:481–490.CrossRefPubMedGoogle Scholar
  35. Nishikawa, T, Edelstein, D, Du, XL, et al (2000) Nature 404:787–790.CrossRefGoogle Scholar
  36. Nogueira, V, Piquet, MA, Devin, A, et al (2001) J Bioenerg Biomembr 33:53–61.CrossRefPubMedGoogle Scholar
  37. Ruch, W, Cooper, PH, Baggiolini, M (1983) J Immunol Methods 63:347–357.CrossRefPubMedGoogle Scholar
  38. Thannickal, VJ, Fanburg, BL (2000) Am J Physiol Lung Cell Mol Physiol 279:L1005–L1028.PubMedGoogle Scholar
  39. Turrens, JF (1997) Biosci Rep 17:3–8.CrossRefPubMedGoogle Scholar
  40. Vanden Hoek, TL, Becker, LB, Shao, Z, et al (1998) J Biol Chem 273:18092–18098.CrossRefPubMedGoogle Scholar
  41. Vinogradov, AD, Grivennikova, VG (2001) IUBMB Life 52:129–134.PubMedCrossRefGoogle Scholar
  42. Vinogradov, AD, Grivennikova, VG (2005) Biochemistry (Mosc) 70:120–127.CrossRefGoogle Scholar
  43. Votyakova, TV, Reynolds, IJ (2001) J Neurochem 79:266–277.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC. 2006

Authors and Affiliations

  • Cécile Batandier
    • 1
  • Bruno Guigas
    • 1
  • Dominique Detaille
    • 1
  • M. El-Mir
    • 2
  • Eric Fontaine
    • 1
  • M. Rigoulet
    • 3
  • X. M. Leverve
    • 1
    • 4
  1. 1.INSERM E-0221 Bioénergétique Fondamentale et AppliquéeUniversit Joseph FourierGrenobleFrance
  2. 2.Faculty of Pharmacy, Department of Physiology and PharmacologyUniversity of SalamancaSalamancaSpain
  3. 3.Institut de Biochimie et de Génétique Cellulaire de CNRSUniversit de Bordeaux IIBordeaux CedexFrance
  4. 4.Bioénergétique Fondamentale et Appliquée INSERM E-0221Universit Joseph FourierGrenoble CedexFrance

Personalised recommendations