http://www.ncbi.nlm.nih.gov/pubmed/26684010
Gueguen N1,2,3, Desquiret-Dumas V1,2,3, Leman G1,3, Chupin S1,2,3, Baron S4, Nivet-Antoine V4, Vessières E1,3, Ayer A1,3, Henrion D1,3, Lenaers G1,3, Reynier P1,2,3, Procaccio V1,2,3.
Abstract
Resveratrol
is often described as a promising therapeutic molecule for numerous
diseases, especially in metabolic and neurodegenerative disorders. While
the mechanism of action is still debated, an increasing literature
reports that resveratrol regulates the mitochondrial respiratory chain
function. In a recent study we have identified mitochondrial complex I
as a direct target of this molecule. Nevertheless, the mechanisms and
consequences of such an interaction still require further investigation.
In this study, we identified in silico by docking study a binding site
for resveratrol at the nucleotide pocket of complex I. In vitro, using
solubilized complex I, we demonstrated a competition between NAD+ and
resveratrol. At low doses (<5μM), resveratrol stimulated complex I
activity, whereas at high dose (50 μM) it rather decreased it. In vivo,
in brain mitochondria from resveratrol treated young mice, we showed
that complex I activity was increased, whereas the respiration rate was
not improved. Moreover, in old mice with low antioxidant defenses, we
demonstrated that complex I activation by resveratrol led to oxidative
stress. These results bring new insights into the mechanism of action of
resveratrol on mitochondria and highlight the importance of the balance
between pro- and antioxidant effects of resveratrol depending on its
dose and age. These parameters should be taken into account when
clinical trials using resveratrol or analogues have to be designed.
- PMID:
- 26684010
- [PubMed - in process]
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