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; Repiščák, Peter; Paterson, Martin J.; Hassinen, Ilmo; McDougall, Gordon; Rena, Graham (2017-08-26)
Amy R. Cameron, Lisa Logie, Kashyap Patel, Stefan Erhardt, Sandra Bacon, Paul Middleton, Jean Harthill, Calum Forteath, Josh T. Coats, Calum Kerr, Heather Curry, Derek Stewart, Kei Sakamoto, Peter Repiščák, Martin J. Paterson, Ilmo Hassinen, Gordon McDougall, Graham Rena. Metformin selectively targets redox control of complex I energy transduction, Redox Biology, Volume 14, 2018, Pages 187-197, ISSN 2213-2317, https://doi.org/10.1016/j.redox.2017.08.018.
© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).
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. DG5 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.
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