Brazdova 2017 MiP2017

From Bioblast
Brazdova Andrea
Pleiotropic effects of biguanides on mitochondrial reactive oxygen species production.

Link: MiP2017

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

Event: MiP2017


Metformin is widely prescribed as a first-choice anti-hyperglycemic drug for treatment of type 2 diabetes mellitus and recent epidemiological studies demonstrated its utility also in cancer therapy. Despite its beneficial therapeutic effects and long term use in clinical practice, its molecular target, either for anti-hyperglycemic or anti-neoplastic action, remains elusive. However, the body of the research on metformin effect oscillates around mitochondrial metabolism, including the function of oxidative phosphorylation (OXPHOS) apparatus.

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 demonstrated that biguanides non-specifically 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 exceeded cellular concentrations observed during the treatment. In addition, these concentrations of biguanides also triggered burst of reactive oxygen species production which, in combination with pleiotropic OXPHOS inhibition, could be toxic for the organism.

We conclude that the favorable effect of biguanides should probably be associated with subtler mechanism, different from the generalized inhibition of the respiratory chain.

β€’ Bioblast editor: Kandolf G β€’ O2k-Network Lab: CZ Prague Houstek J, CZ Hradec Kralove Cervinkova Z, CZ Prague Kalous M

Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Diabetes 

Tissue;cell: Fat  Preparation: Isolated mitochondria 

Pathway: F, N, NS  HRR: Oxygraph-2k 


Affiliations and support

Dept Bioenergetics, Inst Physiology, Czech Academy Sciences, Prague, Czech Republic. - [email protected]
Supported by the Grant Agency of the Czech Republic (16-12726S).
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