PGC-1a Is a Master Regulator of Mitochondrial Lifecycle and ROS Stress Response

Mitochondria play a major role in ROS production and defense during their life cycle. The transcriptional activator PGC-1a is a key player in the homeostasis of energy metabolism and is therefore closely linked to mitochondrial function. PGC-1a responds to environmental and intracellular conditions and is regulated by SIRT1/3, TFAM, and AMPK, which are also important regulators of mitochondrial biogenesis and function. In this review, we highlight the functions and regulatory mechanisms of PGC-1a within this framework, with a focus on its involvement in the mitochondrial lifecycle and ROS metabolism. As an example, we show the role of PGC-1a in ROS scavenging under inflammatory conditions. Interestingly, PGC-1a and the stress response factor NF-?B, which regulates the immune response, are reciprocally regulated. During inflammation, NF-?B reduces PGC-1a expression and activity. Low PGC-1a activity leads to the downregulation of antioxidant target genes resulting in oxidative stress. Additionally, low PGC-1a levels and concomitant oxidative stress promote NF-?B activity, which exacerbates the inflammatory response.