Beneficial effects of resveratrol on respiratory chain defects in patients fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling

Mitochondrial respiratory chain (RC) disorders are the most prevalent inborn metabolic diseases and remain without effective treatment to date. Up-regulation of residual enzyme activity has been proposed as a possible therapeutic approach in this group of disorders. As resveratrol (RSV), a natural compound, was proposed to stimulate mitochondrial metabolism in rodents, we tested the effect of this compound on mitochondrial functions in control or in Complex I (CI)- or Complex IV (CIV)-deficient patients fibroblasts. We show that RSV stimulates the expression of a panel of proteins representing structural subunits or assembly factors of the five RC complexes, in control fibroblasts. In moderate RC-deficient patients cells, RSV treatment increases the amount of mutated proteins and stimulates residual enzyme activities. In these patients cells, we establish that up-regulation of RC enzyme activities induced by RSV translates into increased cellular O-2 consumption rates and results in the correction of RC deficiencies. Importantly, RSV also prevents the accumulation of lactate that occurred in RC-deficient fibroblasts. Different complementary approaches demonstrate that RSV induces a mitochondrial biogenesis that might underlie the increase in mitochondrial capacities. Finally, we showed that, in human fibroblasts, RSV stimulated mitochondrial functions mainly in a SIRT1- and AMPK-independent manner and that its effects rather involved the estrogen receptor (ER) and estrogen-related receptor alpha (ERR) signaling pathways. These results represent the first demonstration that RSV could have a beneficial effect on inborn CI and CIV deficiencies from nuclear origin, in human fibroblasts and might be clinically relevant for the treatment of some RC deficiencies.