TY - JOUR

T1 - Metformin selectively targets redox control of complex I energy transduction

AU - Cameron, Amy R.

AU - Logie, Lisa

AU - Patel, Kashyap

AU - Erhardt, Stefan

AU - Bacon, Sandra

AU - Middleton, Paul

AU - Harthill, Jean

AU - Forteath, Calum

AU - Coats, Josh T.

AU - Kerr, Calum

AU - Curry, Heather

AU - Stewart, Derek

AU - Sakamoto, Kei

AU - Repiščák, Peter

AU - Paterson, Martin J.

AU - Hassinen, Ilmo

AU - McDougall, Gordon

AU - Rena, Graham

PY - 2018/4

Y1 - 2018/4

N2 - 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.

AB - 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.

KW - Diabetes

KW - Metformin

KW - Mitochondria

KW - NAD+

KW - NADH

UR - http://www.scopus.com/inward/record.url?scp=85029574250&partnerID=8YFLogxK

U2 - 10.1016/j.redox.2017.08.018

DO - 10.1016/j.redox.2017.08.018

M3 - Journal article

C2 - 28942196

AN - SCOPUS:85029574250

VL - 14

SP - 187

EP - 197

JO - Redox Biology

JF - Redox Biology

SN - 2213-2317

ER -