Transcriptional control of energy homeostasis through the PGC1 coactivators.

The PGC1 transcriptional coactivators are major regulators of several crucial aspects of energy metabolism. PGC1alpha controls many aspects of oxidative metabolism, including mitochondrial biogenesis and respiration through the coactivation of many nuclear receptors, and factors outside the nuclear receptor family. ERRalpha, NRF1 and NRF2 are key targets of the PGC1s in mitochondrial biogenesis. We have recently addressed the question of the role of PGC1 coactivators in the metabolism of reactive oxygen species (ROS). We now show that PGC1alpha and beta are induced when cells are given an oxidative stressor, H2O2. In fact, experiments with RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins like catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat. Mice deficient in PGC1alpha get excessive neurodegeneration when given kainic acid-induced seizures or MPTP, which causes Parkinsonism. These data show that the PGC1s are important protective molecules against ROS generation and damage. The implications of this for diabetes and neurodegenerative diseases will be discussed.