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

Nitric oxide (NO) has both prooxidant and antioxidant activities in the endothelium; however, the molecular mechanisms involved are still a matter of controversy. PGC-1 alpha [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-1 alpha expression. Short-term (< 12 h) treatment of endothelial cells with NO donors down-regulates PGC-1 alpha expression, whereas long-term (> 24 h) treatment up-regulates it. Treatment with the NOS inhibitor L-NAME has the opposite effect. Downregulation of PGC-1 alpha 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-BrcGMP. Changes in PGC-1 alpha expression are in all cases paralleled by corresponding variations in the mitochondrial ROS detoxification system. Cells that transiently overexpress PGC-1 alpha from the cytomeglovirus (CMV) promoter respond poorly to NO donors. Analysis of tissues from eNOS(-/-) mice showed reduced levels of PGC-1 alpha and the mitochondrial ROS detoxification system. These data suggest that NO can regulate the mitochondrial ROS detoxification system both positively and negatively through PGC-1 alpha. -Borniquel, S., Valle, I., Cadenas, S., Lamas, S., and Monsalve, M. Nitric oxide regulates mitochondrial oxidative stress protection via the transcriptional coactivator PGC-1 alpha.