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.
Highlights
Metformin is the most widely used frontline drug for treatment of type II diabetes mellitus [1, 2]
Given the conflicting reports regarding the molecular target of biguanides in mitochondria, in this study, we addressed the direct impact of biguanides metformin and phenformin on NDH, succinate dehydrogenase (SDH), and mGPDH, mitochondrial glycerophosphate dehydrogenases, which feed electrons into respiratory chain and were proposed to be a target of these drugs
The direct mechanistic knowledge on how biguanides influence mitochondrial function is not yet clear. While their inhibitory effect on NADH dehydrogenase received most attention [8, 23, 24], it was reported that biguanides can inhibit other dehydrogenases in the mitochondrial respiratory chain, namely, succinate dehydrogenase (SDH) [10] and mitochondrial glycerophosphate dehydrogenase [7]
Summary
Metformin (dimethyl biguanide) is the most widely used frontline drug for treatment of type II diabetes mellitus [1, 2]. Some of the proposed mechanisms oscillate around AMP-activated protein kinase (AMPK) activation, which in itself was suggested as a direct target for biguanides [5, 9]. Precise molecular mechanism of its action remains questionable [10, 11]. Metformin utility was explored in the model of heart failure where epidemiologic evidence suggests its protective effect [12, 13]. At the molecular level, a direct effect on mitochondria is observed in some cases [14], but not in others [15]
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