Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production

0484402 - FGÚ 2018 RIV US eng J - Journal Article
Pecinová, Alena - Drahota, Zdeněk - Kovalčíková, Jana - Kovářová, Nikola - Pecina, Petr - Alán, Lukáš - Zima, Michal - Houštěk, Josef - Mráček, Tomáš
Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production.
Oxidative Medicine and Cellular Longevity. Roč. 2017, č. 2017 (2017), č. článku 7038603. ISSN 1942-0900. E-ISSN 1942-0994
R&D Projects: GA ČR(CZ) GA16-12726S; GA MŠMT(CZ) LL1204
Institutional support: RVO:67985823
Keywords : brown adipose tissue * mitochondria * respiratory chain oxidoreductases * mitochondrial glycerophosphate dehydrogenase * superoxide production * biguanides * metformin
OECD category: Biochemistry and molecular biology
Impact factor: 4.936, year: 2017

Metformin is widely prescribed as a first-choice antihyperglycemic drug for treatment of type 2 diabetes mellitus, and additionally recent epidemiological studies showed its utility in cancer therapy. Although it is in use since the 1970s, its molecular target, either for antihyperglycemic or antineoplastic action, remains elusive. 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 (0.01 – 0.1 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.
Permanent Link: http://hdl.handle.net/11104/0279565