Metformin selectively targets redox control of complex I energy transduction

Cameron, Amy R.; Logie, Lisa; Patel, Kashyap; Erhardt, Stefan; Bacon, Sandra; Middleton, Paul; Harthill, Jean; Forteath, Calum; Coats, Josh T.; Kerr, Calum; Curry, Heather; Stewart, Derek; Sakamoto, Kei; Repi�?�k, Peter; Paterson, Martin J.; Hassinen, Ilmo; McDougall, Gordon; Rena, Graham

Abstract

Many guanide-containing drugs are antihyperglycaemic but most exhibit toxicity, to the extent that only the biguanide metformin has enjoyed sustained clinical use. Here, we have isolated unique mitochondrial redox control properties of metformin that are likely to account for this difference. In primary hepatocytes and H4IIE hepatoma cells we found that antihyperglycaemic diguanides DG5-DG10 and the biguanide phenformin were up to 1000-fold more potent than metformin on cell signalling responses, gluconeogenic promoter expression and hepatocyte glucose production. Each drug inhibited cellular oxygen consumption similarly but there were marked differences in other respects. All diguanides and phenformin but not metformin inhibited NADH oxidation in submitochondrial particles, indicative of complex I inhibition, which also corresponded closely with dehydrogenase activity in living cells measured by WST-1. Consistent with these findings, in isolated mitochondria, DG8 but not metformin caused the NADH/NAD+ couple to become more reduced over time and mitochondrial deterioration ensued, suggesting direct inhibition of complex I and mitochondrial toxicity of DG8. In contrast, metformin exerted a selective oxidation of the mitochondrial NADH/NAD+ couple, without triggering mitochondrial deterioration. Together, our results suggest that metformin suppresses energy transduction by selectively inducing a state in complex I where redox and proton transfer domains are no longer efficiently coupled.

Citation

Cameron, A. R., Logie, L., Patel, K., Erhardt, S., Bacon, S., Middleton, P., Harthill, J., Forteath, C., Coats, J. T., Kerr, C., Curry, H., Stewart, D., Sakamoto, K., Repiščák, P., Paterson, M. J., Hassinen, I., McDougall, G., & Rena, G. (2018). Metformin selectively targets redox control of complex I energy transduction. Redox Biology, 14, 187-197. https://doi.org/10.1016/j.redox.2017.08.018

• Journal Article Type: Article
• Acceptance Date: Aug 25, 2017
• Online Publication Date: Aug 26, 2017
• Publication Date: 2018-04
• Deposit Date: Jan 25, 2019
• Publicly Available Date: Jan 25, 2019
• Journal: Redox Biology
• Print ISSN: 2213-2317
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 14
• Pages: 187-197
• DOI: https://doi.org/10.1016/j.redox.2017.08.018
• Keywords: Diabetes, Metformin, Mitochondria, NADH, NAD+,
• Public URL: http://researchrepository.napier.ac.uk/Output/1438399
• Contract Date: Jan 25, 2019