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Oxidative Medicine and Cellular Longevity
Volume 2017, Article ID 7038603, 11 pages
https://doi.org/10.1155/2017/7038603
Research Article

Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production

Institute of Physiology of the Czech Academy of Sciences, Vídeňská, 1083 Prague, Czech Republic

Correspondence should be addressed to Tomas Mracek; zc.sac.ugf@kecarm.samot

Received 29 March 2017; Accepted 13 June 2017; Published 9 August 2017

Academic Editor: Jacek Zielonka

Copyright © 2017 Alena Pecinova et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Metformin is widely prescribed as a first-choice antihyperglycemic drug for treatment of type 2 diabetes mellitus, and recent epidemiological studies showed its utility also in cancer therapy. Although it is in use since the 1970s, its molecular target, either for antihyperglycemic or antineoplastic action, remains elusive. However, the body of the research on metformin effect oscillates around mitochondrial metabolism, including the function of oxidative phosphorylation (OXPHOS) apparatus. In this study, we focused on direct inhibitory mechanism of biguanides (metformin and phenformin) on OXPHOS complexes and its functional impact, using the model of isolated brown adipose tissue mitochondria. We demonstrate that biguanides nonspecifically target the activities of all respiratory chain dehydrogenases (mitochondrial NADH, succinate, and glycerophosphate dehydrogenases), but only at very high concentrations (10−2–10−1 M) that highly exceed cellular concentrations observed during the treatment. In addition, these concentrations of biguanides also trigger burst of reactive oxygen species production which, in combination with pleiotropic OXPHOS inhibition, can be toxic for the organism. We conclude that the beneficial effect of biguanides should probably be associated with subtler mechanism, different from the generalized inhibition of the respiratory chain.