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Metformin Selectively Targets Redox Control of Complex I Energy Transduction Heriot-Watt University Research Gateway Metformin selectively targets redox control of complex I energy transduction Citation for published version: Cameron, AR, Logie, L, Patel, K, Erhardt, S, Bacon, S, Middleton, P, Harthill, J, Forteath, C, Coats, JT, Kerr, C, Curry, H, Stewart, D, Sakamoto, K, Repišák, P, Paterson, MJ, Hassinen, I, McDougall, GJ & Rena, G 2018, 'Metformin selectively targets redox control of complex I energy transduction', Redox Biology, vol. 14, pp. 187-197. https://doi.org/10.1016/j.redox.2017.08.018 Digital Object Identifier (DOI): 10.1016/j.redox.2017.08.018 Link: Link to publication record in Heriot-Watt Research Portal Document Version: Publisher's PDF, also known as Version of record Published In: Redox Biology General rights Copyright for the publications made accessible via Heriot-Watt Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy Heriot-Watt University has made every reasonable effort to ensure that the content in Heriot-Watt Research Portal complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 24. Sep. 2021 Redox Biology 14 (2018) 187–197 Contents lists available at ScienceDirect Redox Biology journal homepage: www.elsevier.com/locate/redox Research paper Metformin selectively targets redox control of complex I energy transduction MARK Amy R. Camerona,1, Lisa Logiea,1, Kashyap Patela,b,2, Stefan Erhardtc,3, Sandra Bacona,d, Paul Middletona,d, Jean Harthilla, Calum Forteatha, Josh T. Coatsa,d, Calum Kerra,d, Heather Currya,d, Derek Stewartd,e, Kei Sakamotob,4, Peter Repiščákc,5, Martin J. Patersonc, ⁎ Ilmo Hassinenf, Gordon McDougalld, Graham Renaa, a Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK b MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, Scotland, UK c Institute of Chemical Sciences, School of Engineering & Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, Scotland, UK d Environmental and Biochemical Sciences, The James Hutton Institute, Invergowrie, Dundee DD2 5DA, Scotland, UK e Institute of Mechanical, Process and Energy Engineering, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, Scotland, UK f Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland ARTICLE INFO ABSTRACT Keywords: Many guanide-containing drugs are antihyperglycaemic but most exhibit toxicity, to the extent that only the Diabetes biguanide metformin has enjoyed sustained clinical use. Here, we have isolated unique mitochondrial redox Metformin control properties of metformin that are likely to account for this difference. In primary hepatocytes and H4IIE Mitochondria hepatoma cells we found that antihyperglycaemic diguanides DG5-DG10 and the biguanide phenformin were up NADH to 1000-fold more potent than metformin on cell signalling responses, gluconeogenic promoter expression and NAD+ 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 oxi- dation 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 mi- tochondria, 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 trig- gering 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. 1. Introduction Unlike biguanides, in diguanides, the two guanidine groups are sepa- rated by an alkyl chain of variable length (Fig. 1). In this series, anti- Recently we have been using analogues of metformin to study how hyperglycaemic effects were found to increase, in proportion with cellular effects of metformin relate to its chemical properties, which toxicity, up to a linker size of 10–12 carbons [10,11]. To achieve the include a strongly hydrophilic character, metal-binding and a pKa maximum effect, the most potent and toxic diguanide, (N,N'-1,10-De- within the physiological pH range [1–6]. This collection of properties is canediylbisguanidine, synthalin A, termed DG10 in our study, Fig. 1b) not shared by other guanidine-containing compounds although many was used in humans but caused liver toxicity [12]. Owing to this failure, do have mitochondrial and antihyperglycaemic effects. In the 1920s for there has been little investigation of the mechanism of action of syn- example, before the discovery of biguanides [7,8], related compounds thalins. Although the mechanism of antihyperglycaemic effects is known as diguanides [9] were briefly evaluated as antidiabetic agents. poorly understood for either drug class, inhibition of mitochondrial ⁎ Corresponding author. E-mail address: [email protected] (G. Rena). 1 These authors contributed equally to this research. 2 Current address: University of Exeter Medical School, RILD Building, RD & E Hospital, Wonford, Barrack Road, Exeter, EX2 5DW, UK. 3 Current address: School of Life, Sport and Social Sciences, Edinburgh Napier University, Edinburgh, Scotland, UK. 4 Current address: Nestlé Institute of Health Sciences SA, EPFL Innovation Park, bâtiment G, 1015 Lausanne, Switzerland. 5 Current address: Beatson Institute for Cancer Research, University of Glasgow, Garscube Estate Switchback Road, Bearsden G61 1QH, UK. http://dx.doi.org/10.1016/j.redox.2017.08.018 Received 30 June 2017; Received in revised form 15 August 2017; Accepted 25 August 2017 Available online 26 August 2017 2213-2317/ © 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/). A.R. Cameron et al. Redox Biology 14 (2018) 187–197 Fig. 1. Comparison of biguanide and diguanide compounds on cells. Structures of biguanides (a) and diguanides (b) are shown. (c, d) H4IIE liver cells had serum removed for 2 h and then were treated with the compounds shown for 3 h, prior to lysis and SDS-PAGE as detailed in the Methods. Immunoblotting was performed using two ACC an- tibodies, one that detects ACC phosphorylated on Ser79 (pACC Ser 79) and another that detects ACC whether or not it is phosphorylated. A third antibody detects AMPK when it is phosphorylated on Thr 172 (pAMPK Thr 172) and a fourth detects AMPK whe- ther or not it is phosphorylated. Finally two anti- bodies that detect S6 protein were used. One detects S6 phosphorylation of residues 240 and 244 (pS6 240/244), whilst a second detects S6 regardless of phosphorylation. For each section, the phosphoryla- tion responses shown are representative of observa- tions from at least three similar experiments. Quantitation of replicates by densitometry appears in the supplementary Fig. 1. respiration has been observed in response to both diguanides and bi- suppression of redox transfer by mitochondrial glycerophosphate de- guanides [13,14]. Early studies suggested that mitochondrial effects hydrogenase (mGPD) [27]. For mGPD, it has been argued elsewhere might be due to the ability of guanidine compounds to alter the func- that effects on glucose production might require additional inhibition of tional and physical structure of membranes [15,16]; however, this the alternative redox malate/aspartate shuttle [28]. None of these model does not readily account for the widely differing toxicities and models readily explain the suppression of weight gain that is one of the potencies of diguanides compared with biguanides and in addition key clinical hallmarks of metformin treatment [29]. metformin is one of the most hydrophilic biguanides, unlikely to in- Recent work on complex I has found evidence for different modes of teract significantly with membranes. Later studies suggested that met- complex regulation by metformin compared with rotenone, which is a formin acts by inhibiting complex I in the electron transport chain neurotoxic complex I inhibitor [30]. In the current study we have in- [14,17]. Mitochondrial suppression by metformin activates AMPK vestigated differences between the actions of metformin, diguanides [18–20], which has emerged as a common cellular response to bigua- and other guanide containing drugs, as these differences might ulti- nides, thiazolidinediones and salicylates [19,21–23]; however, there mately explain the lower toxicity of metformin compared with other are other possible targets, some of which are AMPK-independent. These electron transport chain inhibitors. Investigating the impact of these include regulation of glucose 6-phosphate levels [24], depho- agents on cellular oxygen consumption, gluconeogenic gene regulation, sphorylation of the ribosomal protein S6 by metformin [25,26] and signalling and glucose production,
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