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.
Metformin selectively targets redox control of complex I energy transduction
|Author:||Cameron, Amy R.1; Logie, Lisa1; Patel, Kashyap1,2,3;|
1Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK
2MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, Scotland, UK
3Current address: University of Exeter Medical School, RILD Building, RD & E Hospital, Wonford, Barrack Road, Exeter, EX2 5DW, UK
4Institute of Chemical Sciences, School of Engineering & Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, Scotland, UK
5Current address: School of Life, Sport and Social Sciences, Edinburgh Napier University, Edinburgh, Scotland, UK
6Environmental and Biochemical Sciences, The James Hutton Institute, Invergowrie, Dundee DD2 5DA, Scotland, UK
7Institute of Mechanical, Process and Energy Engineering, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, Scotland, UK
8Current address: Nestlé Institute of Health Sciences SA, EPFL Innovation Park, bâtiment G, 1015 Lausanne, Switzerland
9Current address: Beatson Institute for Cancer Research, University of Glasgow, Garscube Estate Switchback Road, Bearsden G61 1QH, UK
10Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 2.2 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe201803135966
|Publish Date:|| 2018-03-13
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.
|Pages:||187 - 197|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
3121 Internal medicine
G.R. acknowledges funding from the UK Medical Research Council (MRC) (MR/K012924/1) and the Diabetes UK RW and JM Collins studentship, supporting C.F. (12/0004625). S.B. was supported by a Ph.D. studentship from the Rank Prize Funds to G.R., with additional support provided by the University of Dundee. K.P. was supported by a Wellcome Trust Clinical Ph.D. studentship. The research was also supported by further grants from Tenovus Scotland (G.R.), by the MRC (K.S.). D.S. and G.McD. acknowledge funding from The Scottish Government's Rural and Environment Science and Analytical Services Division. MJP acknowledges support from the Engineering and Physical Sciences Research Council (EPSRC) through platform grant EP/P001459/1.
© 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/).