Resveratrol attenuates oxidative stress in mitochondrial Complex I deficiency: Involvement of SIRT3

Abstract

The pathophysiological mechanisms underlying Complex I (CI) deficiencies are understood only partially which severely limits the treatment of this common, devastating, mitochondrial disorder. Recently, we have shown that resveratrol (RSV), a natural polyphenol, has beneficial effects on CI deficiency of nuclear origin. Here, we demonstrate that RSV is able to correct the biochemical defect in oxygen consumption in five of thirteen CI-deficient patient cell lines. Other beneficial effects of RSV include a decrease of total intracellular ROS and the up-regulation of the expression of mitochondrial superoxide dismutase (SOD2) protein, a key antioxidant defense enzyme. The molecular mechanisms leading to the up-regulation of SOD2 protein expression by RSV require the estrogen receptor (ER) and the estrogen-related receptor alpha (ERRα). Although RSV increases the level of SOD2 protein in patients' fibroblasts, the enzyme activity is not increased, in contrast to normal fibroblasts. This led us to hypothesize that SOD2 enzyme activity is regulated post-translationally. This regulation involves SIRT3, a mitochondrial NAD(+)-dependent deacetylase and is critically dependent on NAD(+) levels. Taken together, our data show that the metabolic effects of RSV combined with its antioxidant capacities makes RSV particularly interesting as a candidate molecule for the therapy of CI deficiencies.

Resveratrol ameliorates depressive disorder through the NETRIN1-mediated extracellular�signal-regulated kinase/cAMP signal transduction pathway

“…Oxidative stress and inflammatory markers also have been associated with depression and nicotine dependence (35). A study by Mathieu et al indicated that resveratrol attenuated oxidative stress in mitochondrial complex I deficiency through regulation of the sirtuin 3 signaling pathway (36). In the present study, it was observed that resveratrol treatment attenuated oxidative stress in hippocampal neuron cells, which may have contributed to the recovery in depressive disorder.…”

Development of Therapeutics That Induce Mitochondrial Biogenesis for the Treatment of Acute and Chronic Degenerative Diseases

“…Compound 1 also attenuates oxidative stress in fibroblasts from patients with Complex I deficiency by increasing SOD2 in a SIRT3-dependent manner. 83 Human clinical trials using 1 demonstrated improved lipid profiles, antioxidant defenses, and vascular reactivity in diabetic and obese subjects; 84–89 however, there are conflicting data regarding the effect of 1 on insulin sensitivity, 84, 88, 90 and 1 had no effect in non-obese subjects. 91 …”

Effect of Resveratrol on Sirtuins, OPA1, and Fis1 Expression in Adult Zebrafish Retina

“…Previous reports showed that resveratrol reduced oxidative stress under SIRT3 control in mitochondrial complex I deficiency. 46 In human vascular endothelial cells, resveratrol also maintained mitochondrial reactive oxygen species homeostasis through activation of the SIRT3 signaling pathway. 47 An interesting and novel finding of our study was that the effect of resveratrol on SIRT4 gene expression increased 15-fold when compared to control, and protein expression highly increased in the zebrafish retina.…”