Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria

Biochemical Journal

Volumn 462, Issue 3, 2014, Pages 475-487

  Bridges, Hannah R ^a   Jones, Andrew J Y ^a   Pollak, Michael N ^b   Hirst, Judy ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b MCGILL UNIVERSITY   (Canada)

Author keywords

ATP synthase; Biguanide; Complex I; Metformin; Nadh:quinone oxidoreductase; Reactive oxygen species (ROS)

Indexed keywords

BUFORMIN; CYCLOGUANIL; CYTOCHROME C OXIDASE; HYDROGEN PEROXIDE; METFORMIN; PHENFORMIN; PROGUANIL; PROTON TRANSPORTING ADENOSINE TRIPHOSPHATE SYNTHASE; QUERCETIN; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE DEHYDROGENASE (UBIQUINONE); UBIQUINOL CYTOCHROME C REDUCTASE; UBIQUINONE;

ANIMAL TISSUE; ARTICLE; CATALYSIS; CONTROLLED STUDY; DRUG ACCUMULATION; DRUG PROTEIN BINDING; DRUG UPTAKE; ENZYME INHIBITION; HUMAN; HUMAN CELL; HYDROLYSIS; MITOCHONDRION; NONHUMAN; OXIDATIVE PHOSPHORYLATION; PRIORITY JOURNAL;

ANIMALS; ANTIMALARIALS; ANTINEOPLASTIC AGENTS; BIGUANIDES; CATTLE; DIABETES MELLITUS, TYPE 2; ELECTRON TRANSPORT COMPLEX I; HEP G2 CELLS; HUMANS; METFORMIN; MITOCHONDRIA, HEART; MITOCHONDRIA, LIVER; MITOCHONDRIAL PROTON-TRANSLOCATING ATPASES; OXIDATIVE PHOSPHORYLATION; PLASMODIUM; PROGUANIL; RATS; REPERFUSION INJURY; TRIAZINES;

EID: 84907370814     PISSN: 02646021     EISSN: 14708728     Source Type: Journal    
DOI: 10.1042/BJ20140620     Document Type: Article

References (75)

1. Shaw, R. J., Lamia, K. A., Vasquez, D., Koo, S.-H., Bardeesy, N., DePinho, R. A., Montminy, M. and Cantley, L. C. (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642-1646
2. Miller, R. A., Chu, Q., Xie, J., Foretz, M., Viollet, B. and Birnbaum, M. J. (2013) Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494, 256-260
3. Madiraju, A. K., Erion, D. M., Rahimi, Y., Zhang, X.-M., Braddock, D. T., Albright, R. A., Prigaro, B. J., Wood, J. L., Bhanot, S., MacDonald, M. J. et al. (2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542-546
4. Pollak, M. N. (2012) Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov. 2, 778-790
5. Pernicova, I. and Korbonits, M. (2014) Metformin-mode of action and clinical implications for diabetes and cancer. Nat. Rev. Endocrinol. 10, 143-156
6. Yin, M., van der Horst, I. C. C., van Melle, J. P., Qian, C., van Gilst, W. H., Silljé, H. H. W. and de Boer, R. A. (2011) Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure. Am. J. Physiol. Heart Circ. Physiol. 301, H459-H468
7. Owen, M. R., Doran, E. and Halestrap, A. P. (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex I of the mitochondrial respiratory chain. Biochem. J. 348, 607-614
8. Dykens, J. A., Jamieson, J., Marroquin, L., Nadanaciva, S., Billis, P. A. and Will, Y. (2008) Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol. Appl. Pharm. 233, 203-210
9. Wheaton, W. W., Weinberg, S. E., Hamanaka, R. B., Soberanes, S., Sullivan, L. B., Anso, E., Glasauer, A., Dufour, E., Mutlu, G. M., Budigner, G. R. S. and Chandel, N. S. (2014) Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife 3, e02242
10. Hawley, S. A., Ross, F. A., Chevtzoff, C., Green, K. A., Evans, A., Fogarty, S., Towler, M. C., Brown, L. J., Ogunbayo, O. A., Evans, A. M. and Hardie, D. G. (2010) Use of cells expressing ? -subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 11, 554-565
11. Green, B. D., Irwin, N., Duffy, N. A., Gault, V. A., O'Harte, F. P. M. and Flatt, P. R. (2006) Inhibition of dipeptidyl peptidase-IV activity by metformin enhances the antidiabetic effects of glucagon-like peptide-1. Eur. J. Pharmacol. 547, 192-199
12. Ouyang, J., Parakhia, R. A. and Ochs, R. S. (2011) Metformin activates AMP kinase through inhibition of AMP deaminase. J. Biol. Chem. 286, 1-11
13. Salani, B., Marini, C., del Rio, A., Ravera, S., Massollo, M., Orengo, A. M., Amaro, A., Passalacqua, M., Maffioli, S., Pfeffer, U. et al. (2013) Metformin impairs glucose consumption and survival in Calu-1 cells by direct inhibition of hexokinase-II. Sci. Rep. 3, 2070
14. Hirst, J. (2013) Mitochondrial complex I. Annu. Rev. Biochem. 82, 551-575
15. Kussmaul, L. and Hirst, J. (2006) The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc. Natl. Acad. Sci. U.S.A. 103, 7607-7612
16. Murphy, M. P. (2009) How mitochondria produce reactive oxygen species. Biochem. J. 417, 1-13
17. Nattrass, M. and Alberti, K. G. M. M. (1978) Biguanides. Diabetologia 14, 71-74
18. Painter, H. J., Morrisey, J. M., Mather, M. W. and Vaidya, A. B. (2007) Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum. Nature 446, 88-91
19. Vanichtanankul, J., Taweechai, S., Uttamapinant, C., Chitnumsub, P., Vilaivan, T., Yuthavong, Y. and Kamchonwongpaisan, S. (2012) Combined spatial limitation around residues 16 and 108 of Plasmodium falciparum dihydrofolate reductase explains resistance to cycloguanil. Antimicrob. Agents Chemother. 56, 3928-3935
20. Sharpley, M. S., Shannon, R. J., Draghi, F. and Hirst, J. (2006) Interactions between phospholipids and NADH:ubiquinone oxidoreductase (complex I) from bovine mitochondria. Biochemistry 45, 241-248
21. Bridges, H. R., Grgic, L., Harbour, M. E. and Hirst, J. (2009) The respiratory complexes I from the mitochondria of two Pichia species. Biochem. J. 422, 151-159
22. Sazanov, L. A., Carroll, J., Holt, P., Toime, L. and Fearnley, I. M. (2003) A role for native lipids in the stabilization and two-dimensional crystallization of the Escherichia coli NADH:ubiquinone oxidoreductase (complex I). J. Biol. Chem. 278, 19483-19491
23. Pryde, K. R. and Hirst, J. (2011) Superoxide is produced by the reduced flavin in mitochondrial complex I: a single, unified mechanism that applies during both forward and reverse electron transfer. J. Biol. Chem. 286, 18056-18065
24. Chappell, J. B. and Hansford, R. G. (1972) Preparation of mitochondria from animal tissues and yeasts. In Subcellular Components: Preparation and Fractionation, 2nd ed (Birnie, G. D., ed.), pp. 77-91, Butterworths, London
25. 0-ATP synthase from bovine heart mitochondria: development of the purification of a monodisperse oligomycin-sensitive ATPase. Biochem. J. 295, 799-806
26. + , ferricyanide or molecular oxygen. Biochemistry 48, 12005-12013
27. Birrell, J. A., King, M. S. and Hirst, J. (2011) A ternary mechanism for NADH oxidation by positively charged electron acceptors, catalyzed at the flavin site in respiratory complex I. FEBS Lett. 585, 2318-2322
28. Jones, A. J. Y. and Hirst, J. (2013) A spectrophotometric, coupled enzyme assay to measure the activity of succinate dehydrogenase. Anal. Biochem. 442, 19-23
29. Pullman, M. E., Penefsky, H. S., Datta, A. and Racker, E. (1960) Partial resolution of the enzymes catalyzing oxidative phosphorylation. J. Biol. Chem. 235, 3322-3329
30. Danielsson, L.-G. and Zhang, Y.-H. (1996) Methods for determining n-octanol-water partition coefficients. Trends Anal. Chem. 15, 188-196
31. Ray, P. (1961) Complex compounds of biguanides and guanylureas with metallic elements. Chem. Rev. 61, 313-359
32. Forneris, F., Orru, R., Bonivento, D., Chiarelli, L. R. and Mattevi, A. (2009) ThermoFAD, a Thermofluor -adapted flavin ad hoc detection system for protein folding and ligand binding. FEBS J. 276, 2833-2840
33. Birrell, J. A., Morina, K., Bridges, H. R., Friedrich, T. and Hirst, J. (2013) Investigating the function of [2Fe-2S] cluster N1a, the off-pathway cluster in complex I, by manipulating its reduction potential. Biochem. J. 456, 139-146
34. Holford, N. H. G. and Sheiner, L. B. (1981) Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin. Pharmacokinet. 6, 429-453
35. Grivennikova, V. G. and Vinogradov, A. D. (2013) Partitioning of superoxide and hydrogen peroxide production by mitochondrial respiratory complex I. Biochim. Biophys. Acta 1827, 446-454
36. II-DTPA, a very low potential reductant. Biochemistry 47, 8885-8893
37. Briggs, G. E. and Haldane, J. B. S. (1925) A note on the kinetics of enzyme action. Biochem. J. 19, 338-339
38. Baradaran, R., Berrisford, J. M., Minhas, G. S. and Sazanov, L. A. (2013) Crystal structure of the entire respiratory complex I. Nature 494, 443-448
39. Galkin, A., Meyer, B., Wittig, I., Karas, M., Schägger, H., Vinogradov, A. and Brandt, U. (2008) Identification of the mitochondrial ND3 subunit as a structural component involved in the active/deactive enzyme transition of respiratory complex I. J. Biol. Chem. 283, 20907-20913
40. + antiporter. J. Biol. Chem. 287, 34743-34751
41. Kalia, J. and Swartz, K. J. (2011) Elucidating the molecular basis of action of a classic drug: guanidine compounds as inhibitors of voltage-gated potassium channels. Mol. Pharmacol. 80, 1085-1095
42. Hatefi, Y., Stempel, K. E. and Hanstein, W. G. (1969) Inhibitors and activators of the mitochondrial reduced diphosphopyridine nucleotide dehydrogenase. J. Biol. Chem. 244, 2358-2365
43. Hirst, J., Carroll, J., Fearnley, I. M., Shannon, R. J. and Walker, J. E. (2003) The nuclear encoded subunits of complex I from bovine heart mitochondria. Biochim. Biophys. Acta 1604, 135-150
44. Sled, V. D., Rudnitzky, N. I., Hatefi, Y. and Ohnishi, T. (1994) Thermodynamic analysis of flavin in mitochondrial NADH:ubiquinone oxidoreductase (complex I). Biochemistry 33, 10069-10075
45. Carvalho, C., Correia, S., Santos, M. S., Seiça, R., Oliveira, C. R. and Moreira, P. I. (2008) Metformin promotes isolated rat liver mitochondria impairment. Mol. Cell. Biochem. 308, 75-83
46. Zou, M.-H., Kirkpatrick, S. S., Davis, B. J., Nelson, J. S., Wiles, W. G., Schlattner, U., Neumann, D., Brownlee, M., Freeman, M. B. and Goldman, M. H. (2004) Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo: role of mitochondrial reactive nitrogen species. J. Biol. Chem. 279, 43940-43951
47. MacKenzie, R. M., Salt, I. P., Miller, W. H., Logan, A., Ibrahim, H. A., Degasper, A., Dymott, J. A., Hamilton, C. A., Murphy, M. P., Delles, C. and Dominiczak, A. F. (2013) Mitochondrial reactive oxygen species enhance AMP-activated protein kinase activation in the endothelium of patients with coronary artery disease and diabetes. Clin. Sci. 124, 403-411
48. Algire, C., Moiseeva, O., Deschênes-Simard, X., Amrein, L., Petruccelli, L., Birman, E., Viollet, B., Ferbeyre, G. and Pollak, M. N. (2012) Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev. Res. 5, 536-543
49. El-Mir, M.-Y., Nogueira, V., Fontaine, E., Avéret, N., Rigoulet, M. and Leverve, X. (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 275, 223-228
50. Drahota, Z., Palenickova, E., Endlicher, R., Milerova, M., Brejchova, J., Vosahlikova, M., Svoboda, P., Kazdova, L., Kalous, M., Cervinkova, Z. and Cahova, M. (2013) Biguanides inhibit complex I, II and IV of rat liver mitochondria and modify their functional properties. Physiol. Res. 63, 1-11
51. Corominas-Faja, B., Quirantes-Piné, R., Oliveras-Ferraros, C., Vazquez-Martin, A., Cufí, S., Martin-Castillo, B., Micol, V., Joven, J., Segura-Carretero, A. and Menendez, J. A. (2012) Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs. Aging 4, 480-496
52. Cabreiro, F., Au, C., Leung, K.-Y., Vergara-Irigaray, N., Cochemé, H. M., Noori, T., Weinkove, D., Schuster, E., Greene, N. D. E. and Gems, D. (2013) Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153, 228-239
53. Monera, O. D., Kay, C. M. and Hodges, R. S. (1994) Protein denaturation with guanidine hydrochloride or urea provides a different estimate of stability depending on the contributions of electrostatic interactions. Protein Sci. 3, 1984-1991
54. England, J. L. and Haran, G. (2011) Role of solvation effects in protein denaturation: from thermodynamics to single molecules and back. Annu. Rev. Phys. Chem. 62, 257-277
55. 1-ATPase from bovine mitochondria. Proc. Natl. Acad. Sci. U.S.A. 104, 15671-15676
56. O ATP hydrolase. Bioorg. Med. Chem. Lett. 14, 1027-1030
57. Schulz, M. and Schmoldt, A. (2003) Therapeutic and toxic blood concentrations of more than 800 drugs and other xenobiotics. Pharmazie 58, 447-474
58. Helsby, N. A., Edwards, G., Breckenridge, A. M. and Ward, S. A. (1993) The multiple dose pharmacokinetics of proguanil. Br. J. Clin. Pharmacol. 35, 653-656
59. Kerb, R., Fux, R., Mörike, K., Kremsner, P. G., Gil, J. P., Gleiter, C. H. and Schwab, M. (2009) Pharmacogenetics of antimalarial drugs: effect on metabolism and transport. Lancet Infect. Dis. 9, 760-764
60. Wang, D.-S., Jonker, J. W., Kato, Y., Kusuhara, H., Schinkel, A. H. and Sugiyama, Y. (2002) Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J. Pharmacol. Exp. Ther. 302, 510-515
61. Segal, E. D., Yasmeen, A., Beauchamp, M.-C., Rosenblatt, J., Pollak, M. and Gotlieb, W. H. (2011) Relevance of the OCT1 transporter to the antineoplastic effect of biguanides. Biochem. Biophys. Res. Commun. 414, 694-699
62. Lamhonwah, A.-M. and Tein, I. (2006) Novel localization of OCTN1, an organic cation/carnitine transporter, to mammalian mitochondria. Biochem. Biophys. Res. Commun. 345, 1315-1325
63. Shitara, Y., Nakamichi, N., Norioka, M., Shima, H., Kato, Y. and Horie, T. (2012) Role of organic cation/carnitine transporter 1 in uptake of phenformin and inhibitory effect on complex I respiration in mitochondria. Toxicol. Sci. 132, 32-42
64. Appleby, R. D., Porteous, W. K., Hughes, G., James, A. M., Shannon, D., Wei, Y.-H. and Murphy, M. P. (1999) Quantitation and origin of the mitochondrial membrane potential in human cells lacking mitochondrial DNA. Eur. J. Biochem. 262, 108-116
65. Galkin, A., Abramov, A. Y., Frakich, N., Duchen, M. R. and Moncada, S. (2009) Lack of oxygen deactivates mitochondrial complex I: implications for ischemic injury? J. Biol. Chem. 284, 36055-36061
66. 1. Cell Metab. 8, 13-25
67. Chen, Q., Camara, A. K. S., Stowe, D. F., Hoppel, C. L. and Lesnefsky, E. J. (2007) Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion. Am. J. Physiol. Cell. Physiol. 292, C137-C147
68. Chouchani, E. T., Methner, C., Nadtochiy, S. M., Logan, A., Pell, V. R., Ding, S., James, A. M., Cochemé, H. M., Reinhold, J., Lilley, K. S. et al. (2013) Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat. Med. 19, 753-759
69. O-ATPase: effect of selective pharmacological inhibition of mitochondrial ATPase hydrolase activity. Am. J. Physiol. Heart Circ. Physiol. 287, H1747-H1755
70. Batandier, C., Guigas, B., Detaille, D., El-Mir, M.-Y., Fontaine, E., Rigoulet, M. and Leverve, X. M. (2006) The ROS production induced by a reverse-electron flux at respiratory chain complex I is hampered by metformin. J. Bioenerg. Biomembr. 38, 33-42
71. Paiva, M. A., Rutter-Locher, Z., Gonçalves, L. M., Goncalves, L. M., Providência, L. A., Davidson, S. M., Yellon, D. M. and Mocanu, M. M. (2011) Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 300, H2123-H2134
72. Suissa, S. and Azoulay, L. (2012) Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care 35, 2665-2673
73. Vander Heiden, M. G., Cantley, L. C. and Thompson, C. B. (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029-1033
74. Costello, L. C., Franklin, R. B. and Feng, P. (2005) Mitochondrial function, zinc, and intermediary metabolism relationships in normal prostate and prostate cancer. Mitochondrion 5, 143-153
75. Birsoy, K., Possemato, R., Lorbeer, F. K., Bayraktar, E. C., Thiru, P., Yucel, B., Wang, T., Chen, W. W., Clish, C. B. and Sabatini, D. M. (2014) Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 508, 108-112