Molecular regulation of PGC-1α: from protein-protein interactions and post-translational modifications to...

Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is a master transcriptional coactivator responsible for regulating cellular energy metabolism and mitochondrial biogenesis across high-energy tissues such as the heart, skeletal muscle, and brown adipose tissue. To orchestrate its regulatory functions, PGC-1α interacts with a diverse array of transcription factors such as peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and nuclear respiratory factors (NRFs), which is facilitated by its dynamic three-dimensional structure, the presence of distinct functional domains, and the ability to be modulated via post-translational modifications. This review examines the protein's interactions with key nuclear receptors and the biological consequences of these complexes, including the regulation of thermogenesis, gluconeogenesis, and fatty acid oxidation. Furthermore, we discuss the extensive post-translational modifications-including phosphorylation, acetylation, methylation, O-GlcNAcylation, and ubiquitination-that tightly regulate PGC-1α stability and coactivation efficiency. Finally, this review highlights recent progress in the identification of small molecule modulators, such as the activator ZLN005 and the inhibitor SR18292, evaluating their physiological outcomes and potential as therapeutic agents for metabolic disorders and cancer, while addressing the challenges posed by the protein's structural disorder in drug discovery.