Nitric oxide regulates mitochondrial oxidative stress protection via the transcriptional coactivator PGC-1alpha

FASEB J. 2006 Sep;20(11):1889-91. doi: 10.1096/fj.05-5189fje. Epub 2006 Aug 4.


Nitric oxide (NO) has both prooxidant and antioxidant activities in the endothelium; however, the molecular mechanisms involved are still a matter of controversy. PGC-1alpha [peroxisome proliferators-activated receptor (PPAR) gamma coactivator 1-alpha] induces the expression of several members of the mitochondrial reactive oxygen species (ROS) detoxification system. Here, we show that NO regulates this system through the modulation of PGC-1alpha expression. Short-term (<12 h) treatment of endothelial cells with NO donors down-regulates PGC-1alpha expression, whereas long-term (>24 h) treatment up-regulates it. Treatment with the NOS inhibitor l-NAME has the opposite effect. Down-regulation of PGC-1alpha by NO is mediated by protein kinase G (PKG). It is blocked by the soluble guanylate cyclase (sGC) inhibitor ODQ and the PKG inhibitor KT5823, and mimicked by the cGMP analog 8-Br-cGMP. Changes in PGC-1alpha expression are in all cases paralleled by corresponding variations in the mitochondrial ROS detoxification system. Cells that transiently overexpress PGC-1alpha from the cytomeglovirus (CMV) promoter respond poorly to NO donors. Analysis of tissues from eNOS(-/-) mice showed reduced levels of PGC-1alpha and the mitochondrial ROS detoxification system. These data suggest that NO can regulate the mitochondrial ROS detoxification system both positively and negatively through PGC-1alpha.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta
  • Cattle
  • Cell Culture Techniques
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiology*
  • Heat-Shock Proteins / drug effects
  • Heat-Shock Proteins / genetics*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / physiology*
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / pharmacology*
  • Nitric Oxide Donors / pharmacology*
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Oxygen Consumption / drug effects
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Polymerase Chain Reaction
  • Trans-Activators / drug effects
  • Trans-Activators / genetics*
  • Transcription Factors / drug effects
  • Transcription Factors / genetics*
  • Umbilical Veins


  • Heat-Shock Proteins
  • Nitric Oxide Donors
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Nitric Oxide
  • NG-Nitroarginine Methyl Ester