Pecinova 2017 Oxid Med Cell Longev

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Pecinova A, Drahota Z, Kovalcikova J, Kovarova N, Pecina P, Alan L, Zima M, Houstek J, Mracek T (2017) Pleiotropic effects of biguanides on mitochondrial reactive oxygen species production. Oxid Med Cell Longev 7038603.

» Open Access

Pecinova A, Drahota Z, Kovalcikova J, Kovarova N, Pecina P, Alan L, Zima M, Houstek J, Mracek T (2017) Oxid Med Cell Longev

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.

Keywords: Biguanide, Metformin, Respiratory chain, Reactive oxygen species Bioblast editor: Kandolf G O2k-Network Lab: CZ Hradec Kralove Cervinkova Z, CZ Prague Houstek J, CZ Prague Kalous M


Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Diabetes  Stress:Oxidative stress;RONS  Organism: Rat  Tissue;cell: Fat  Preparation: Isolated mitochondria 


Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, Gp, NS  HRR: Oxygraph-2k 

Labels, 2017-09, Amplex Red