Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F17%3A00484402" target="_blank" >RIV/67985823:_____/17:00484402 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1155/2017/7038603" target="_blank" >http://dx.doi.org/10.1155/2017/7038603</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1155/2017/7038603" target="_blank" >10.1155/2017/7038603</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Oxidative Medicine and Cellular Longevity

ISSN

1942-0900

e-ISSN

—

Svazek periodika

2017

Číslo periodika v rámci svazku

2017

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

11

Strana od-do

—

Kód UT WoS článku

000407199100001

EID výsledku v databázi Scopus

2-s2.0-85028431346