Journal
REDOX BIOLOGY
Volume 14, Issue -, Pages 187-197Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.redox.2017.08.018
Keywords
Diabetes; Metformin; Mitochondria; NADH; NAD
Categories
Funding
- UK Medical Research Council (MRC) [MR/K012924/1]
- Diabetes UK RW and JM Collins studentship [12/0004625]
- Rank Prize Funds
- University of Dundee
- Wellcome Trust
- Tenovus Scotland
- MRC
- Scottish Government's Rural and Environment Science and Analytical Services Division
- Engineering and Physical Sciences Research Council (EPSRC) [EP/P001459/1]
- Wellcome Trust [110082/Z/15/Z] Funding Source: Wellcome Trust
- EPSRC [EP/P001459/1] Funding Source: UKRI
- MRC [MR/K012924/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/P001459/1] Funding Source: researchfish
- Medical Research Council [MR/K012924/1] Funding Source: researchfish
- National Institute for Health Research [CL-2013-23-001] Funding Source: researchfish
- Wellcome Trust [110082/Z/15/Z] Funding Source: researchfish
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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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