Metformin selectively targets redox control of complex I energy transduction

@article{Cameron2018MetforminST,
  title={Metformin selectively targets redox control of complex I energy transduction},
  author={Amy R. Cameron and L. Logie and Kashyap A. Patel and Stefan Erhardt and S. Bacon and P. Middleton and J. Harthill and C. Forteath and Josh T. Coats and Calum Kerr and H. Curry and D. Stewart and K. Sakamoto and Peter Repi{\vs}{\vc}{\'a}k and M. Paterson and I. Hassinen and G. McDougall and G. Rena},
  journal={Redox Biology},
  year={2018},
  volume={14},
  pages={187 - 197}
}
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… Expand
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References

SHOWING 1-10 OF 70 REFERENCES
Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.
TLDR
It is concluded that the drug's pharmacological effects are mediated, at least in part, through a time-dependent, self-limiting inhibition of the respiratory chain that restrains hepatic gluconeogenesis while increasing glucose utilization in peripheral tissues. Expand
Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase
TLDR
It is shown that metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose, and decreased hepatic gluconeogenesis. Expand
Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria
TLDR
It is reported that biguanides inhibit complex I by inhibiting ubiquinone reduction (but not competitively) and, independently, stimulate reactive oxygen species production by the complex I flavin and are identified as a new class of complex I and ATP synthase inhibitor. Expand
Cellular Responses to the Metal-Binding Properties of Metformin
TLDR
It is demonstrated that copper sequestration opposes known actions of metformin not only on AMP-activated protein kinase (AMPK)-dependent signaling, but also on S6 protein phosphorylation, supporting recent data that AMPK and S6 phosphorylated are regulated independently by biguanides. Expand
Molecular features of biguanides required for targeting of mitochondrial respiratory complex I and activation of AMP-kinase
TLDR
Biguanides inhibit mitochondrial complex I, but specific molecular features control the uptake of substituted biguanides into mitochondria, so only some biguanided inhibit mitochondrial respiration in vivo, suggesting that biguanide uptake into mitochondia is protein mediated, and is not by passive diffusion. Expand
Selective inhibition of deactivated mitochondrial complex I by biguanides.
Biguanides are widely used antihyperglycemic agents for diabetes mellitus and prediabetes treatment. Complex I is the rate-limiting step of the mitochondrial electron transport chain (ETC), a majorExpand
Investigation of salicylate hepatic responses in comparison with chemical analogues of the drug
TLDR
Salicylate alone reduced promoter activity of the key gluconeogenic enzyme glucose 6-phosphatase and suppressed basal glucose production in mouse primary hepatocytes, and this finding supports much earlier literature suggesting that salicylates exert anti-hyperglycaemic effects at least in part through uncoupling. Expand
The Effects of Guanidine and Alkylguanidines on the Energy Transfer Reactions of Mitochondria
Considerable attention has been focused on the biological activity of guanidine derivatives from two main directions. Ever since the original report by Watanabe of the hypoglycemic properties ofExpand
The mechanisms of action of metformin
TLDR
Physiologically, metformin has been shown to reduce hepatic glucose production, yet not all of its effects can be explained by this mechanism and there is increasing evidence of a key role for the gut. Expand
Dimethylbiguanide Inhibits Cell Respiration via an Indirect Effect Targeted on the Respiratory Chain Complex I*
TLDR
The results suggest the existence of a new cell-signaling pathway targeted to the respiratory chain complex I with a persistent effect after cessation of the signaling process. Expand
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3
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5
...