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Metformin selectively targets redox control of complex I energy transduction


Amy R. Cameron

Lisa Logie

Kashyap Patel

Sandra Bacon

Paul Middleton

Jean Harthill

Calum Forteath

Josh T. Coats

Calum Kerr

Heather Curry

Derek Stewart

Kei Sakamoto


Martin J. Paterson

Ilmo Hassinen

Gordon McDougall

Graham Rena


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.


Cameron, A. R., Logie, L., Patel, K., Erhardt, S., Bacon, S., Middleton, P., …Rena, G. (2018). Metformin selectively targets redox control of complex I energy transduction. Redox Biology, 14, 187-197.

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
Keywords Diabetes, Metformin, Mitochondria, NADH, NAD+,
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Metformin selectively targets redox control of complex I energy transduction (2.4 Mb)

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Copyright Statement
© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (

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