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

Free Radic Biol Med. 2016 Jul;96:190-8. doi: 10.1016/j.freeradbiomed.2016.04.027. Epub 2016 Apr 25.


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.

Keywords: Complex I deficiency; Mitochondrial diseases; Oxidative stress; Pharmacological therapy; Resveratrol; SIRT3; SOD2.

MeSH terms

  • Antioxidants / metabolism
  • Cells, Cultured
  • Electron Transport Complex I / deficiency*
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism
  • Estrogen Receptor alpha / genetics*
  • Fibroblasts / drug effects
  • Gene Expression Regulation / drug effects
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / genetics
  • Mitochondrial Diseases / drug therapy*
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / metabolism
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Oxygen Consumption / genetics
  • Reactive Oxygen Species / metabolism
  • Receptors, Estrogen / genetics*
  • Resveratrol
  • Signal Transduction / drug effects
  • Sirtuin 3 / genetics*
  • Stilbenes / administration & dosage*
  • Superoxide Dismutase / genetics*


  • Antioxidants
  • ERRalpha estrogen-related receptor
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Reactive Oxygen Species
  • Receptors, Estrogen
  • Stilbenes
  • Superoxide Dismutase
  • superoxide dismutase 2
  • SIRT3 protein, human
  • Sirtuin 3
  • Electron Transport Complex I
  • Resveratrol

Supplementary concepts

  • Mitochondrial complex I deficiency