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Metformin selectively targets redox control of complex I energy transduction
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 pri...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609876/ https://www.ncbi.nlm.nih.gov/pubmed/28942196 http://dx.doi.org/10.1016/j.redox.2017.08.018 |
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author | Cameron, Amy R. Logie, Lisa Patel, Kashyap Erhardt, Stefan Bacon, Sandra Middleton, Paul Harthill, Jean Forteath, Calum Coats, Josh T. Kerr, Calum Curry, Heather Stewart, Derek Sakamoto, Kei Repiščák, Peter Paterson, Martin J. Hassinen, Ilmo McDougall, Gordon Rena, Graham |
author_facet | Cameron, Amy R. Logie, Lisa Patel, Kashyap Erhardt, Stefan Bacon, Sandra Middleton, Paul Harthill, Jean Forteath, Calum Coats, Josh T. Kerr, Calum Curry, Heather Stewart, Derek Sakamoto, Kei Repiščák, Peter Paterson, Martin J. Hassinen, Ilmo McDougall, Gordon Rena, Graham |
author_sort | Cameron, Amy R. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5609876 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-56098762017-10-02 Metformin selectively targets redox control of complex I energy transduction Cameron, Amy R. Logie, Lisa Patel, Kashyap Erhardt, Stefan Bacon, Sandra Middleton, Paul Harthill, Jean Forteath, Calum Coats, Josh T. Kerr, Calum Curry, Heather Stewart, Derek Sakamoto, Kei Repiščák, Peter Paterson, Martin J. Hassinen, Ilmo McDougall, Gordon Rena, Graham Redox Biol Research Paper 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. Elsevier 2017-08-26 /pmc/articles/PMC5609876/ /pubmed/28942196 http://dx.doi.org/10.1016/j.redox.2017.08.018 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Paper Cameron, Amy R. Logie, Lisa Patel, Kashyap Erhardt, Stefan Bacon, Sandra Middleton, Paul Harthill, Jean Forteath, Calum Coats, Josh T. Kerr, Calum Curry, Heather Stewart, Derek Sakamoto, Kei Repiščák, Peter Paterson, Martin J. Hassinen, Ilmo McDougall, Gordon Rena, Graham Metformin selectively targets redox control of complex I energy transduction |
title | Metformin selectively targets redox control of complex I energy transduction |
title_full | Metformin selectively targets redox control of complex I energy transduction |
title_fullStr | Metformin selectively targets redox control of complex I energy transduction |
title_full_unstemmed | Metformin selectively targets redox control of complex I energy transduction |
title_short | Metformin selectively targets redox control of complex I energy transduction |
title_sort | metformin selectively targets redox control of complex i energy transduction |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609876/ https://www.ncbi.nlm.nih.gov/pubmed/28942196 http://dx.doi.org/10.1016/j.redox.2017.08.018 |
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