PGC-1<i>α</i>, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

<jats:p>Peroxisome proliferator-activated receptor-<jats:italic>γ</jats:italic> coactivator (PGC)-1<jats:italic>α</jats:italic> is a transcriptional coactivator described as a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation and reactive oxygen species detoxification. PGC-1<jats:italic>α</jats:italic> is highly expressed in tissues with high energy demands, and it is clearly associated with the pathogenesis of metabolic syndrome and its principal complications including obesity, type 2 diabetes mellitus, cardiovascular disease, and hepatic steatosis. We herein review the molecular pathways regulated by PGC-1<jats:italic>α</jats:italic>, which connect oxidative stress and mitochondrial metabolism with inflammatory response and metabolic syndrome. PGC-1<jats:italic>α</jats:italic> regulates the expression of mitochondrial antioxidant genes, including manganese superoxide dismutase, catalase, peroxiredoxin 3 and 5, uncoupling protein 2, thioredoxin 2, and thioredoxin reductase and thus prevents oxidative injury and mitochondrial dysfunction. Dysregulation of PGC-1<jats:italic>α</jats:italic> alters redox homeostasis in cells and exacerbates inflammatory response, which is commonly accompanied by metabolic disturbances. During inflammation, low levels of PGC-1<jats:italic>α</jats:italic> downregulate mitochondrial antioxidant gene expression, induce oxidative stress, and promote nuclear factor kappa B activation. In metabolic syndrome, which is characterized by a chronic low grade of inflammation, PGC-1<jats:italic>α</jats:italic> dysregulation modifies the metabolic properties of tissues by altering mitochondrial function and promoting reactive oxygen species accumulation. In conclusion, PGC-1<jats:italic>α</jats:italic> acts as an essential node connecting metabolic regulation, redox control, and inflammatory pathways, and it is an interesting therapeutic target that may have significant benefits for a number of metabolic diseases.</jats:p>