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.
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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
REFERENCES
Anderson, WM, Trgovcich-Zacok, D (1995) Biochim Biophys Acta 1230:186–193.
Anonymous (1998) Lancet 352:854–865.
Batandier, C, Leverve, X, Fontaine, E (2004) J Biol Chem 279:17197–17204.
Bernardi, P, Petronilli, V, Di Lisa, F, et al (2001) Trends Biochem Sci 26:112–117.
Boveris, A, Chance, B (1973) Biochem J 134:707–716.
Brownlee, M (2001) Nature 414:813–820.
Chance, B, Hollunger, G (1961a) J Biol Chem 236:1534–1543.
Chance, B, Hollunger, G (1961b) J Biol Chem 236:1562–1568.
Chauvin, C, De Oliveira, F, Ronot, X, et al (2001) J Biol Chem 276:41394–41398.
Desagher, S, Martinou, JC (2000) Trends Cell Biol 10:369–377.
Detaille, D, Guigas, B, Chauvin, C, et al (2005) Diabetes 54:2179–2187.
Droge, W (2002) Physiol Rev 82:47–95.
Du, XL, Edelstein, D, Rossetti, L, et al (2000) Proc Natl Acad Sci U.S.A. 97:12222–12226.
Du, X, Matsumura, T, Edelstein, D, et al (2003) J Clin Invest 112:1049–1057.
El-Mir, MY, Nogueira, V, Fontaine, E, et al (2000) J Biol Chem 275:223–228.
Erecinska, M, Wilson, D F (1982) J Membr Biol 70:1–14.
Fontaine, E, Eriksson, O, Ichas, F, et al (1998) J Biol Chem 273:12662–12668.
Forman, NG, Wilson, DF (1982) J Biol Chem 257:12908–12915.
Guigas, B, Detaille, D, Chauvin, C, et al (2004) Biochem J 382:877–884.
Hill, HD, Straka, JG (1988) Anal Biochem 170:203–208.
Hinkle, PC, Butow, RA, Racker, E, et al (1967) J Biol Chem 242:5169–5173.
Kagawa, Y, Cha, SH, Hasegawa, K, et al (1999) Biochem Biophys Res Commun 266:662–676.
Klingenberg, M, Slenczka, W (1959) Biochem Z 331:486–517.
Korshunov, SS, Korkina, OV, Ruuge, EK, et al (1998) FEBS Lett 435:215–218.
Korshunov, SS, Skulachev, VP, Starkov, AA (1997) FEBS Lett 416:15–18.
Kudin, AP, Bimpong-Buta, NY, Vielhaber, S, et al (2004) J Biol Chem 279:4127–4135.
Kushnareva, Y, Murphy, AN, Andreyev, A (2002) Biochem J 368:545–553.
Kwong, LK, Sohal, RS (1998) Arch Biochem Biophys 350:118–126.
Lambert, AJ, Brand, MD (2004a) J Biol Chem 279:39414–39420.
Lambert, AJ, Brand, MD (2004b) Biochem J 382:511–517.
Lebuffe, G, Schumacker, PT, Shao, ZH, et al (2003) Am J Physiol Heart Circ Physiol 284:H299–H308.
Lee, HC, Wei, YH (2000) J Biomed Sci 7:2–15.
Liu, Y, Fiskum, G, Schubert, D (2002) J Neurochem 80:780–787.
Newmeyer, DD, Ferguson-Miller, S (2003) Cell 112:481–490.
Nishikawa, T, Edelstein, D, Du, XL, et al (2000) Nature 404:787–790.
Nogueira, V, Piquet, MA, Devin, A, et al (2001) J Bioenerg Biomembr 33:53–61.
Ruch, W, Cooper, PH, Baggiolini, M (1983) J Immunol Methods 63:347–357.
Thannickal, VJ, Fanburg, BL (2000) Am J Physiol Lung Cell Mol Physiol 279:L1005–L1028.
Turrens, JF (1997) Biosci Rep 17:3–8.
Vanden Hoek, TL, Becker, LB, Shao, Z, et al (1998) J Biol Chem 273:18092–18098.
Vinogradov, AD, Grivennikova, VG (2001) IUBMB Life 52:129–134.
Vinogradov, AD, Grivennikova, VG (2005) Biochemistry (Mosc) 70:120–127.
Votyakova, TV, Reynolds, IJ (2001) J Neurochem 79:266–277.
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Batandier, C., Guigas, B., Detaille, D. et al. The ROS Production Induced by a Reverse-Electron Flux at Respiratory-Chain Complex 1 is Hampered by Metformin. J Bioenerg Biomembr 38, 33–42 (2006). https://doi.org/10.1007/s10863-006-9003-8
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DOI: https://doi.org/10.1007/s10863-006-9003-8