PGC-1α regulation via protein interactions, PTMs, and small molecules offers metabolic disorder targets

Cellular energy metabolism and mitochondrial biogenesis are fundamental processes, with dysregulation contributing to conditions like metabolic disorders and cancer. Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is a master transcriptional coactivator vital for these processes in high-energy tissues such as the heart and skeletal muscle. Current therapeutic strategies often fall short in precisely modulating these complex pathways. Understanding the intricate molecular mechanisms governing PGC-1α's activity, including its interactions with transcription factors like PPARs and ERRs and its post-translational modifications, is crucial for identifying novel therapeutic targets and developing more effective interventions.

This comprehensive review systematically analyzed current literature on PGC-1α's molecular regulation, synthesizing findings from numerous studies. It examined PGC-1α's dynamic interactions with key nuclear receptors, including peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and nuclear respiratory factors (NRFs), and the biological consequences of these complexes, such as the regulation of thermogenesis, gluconeogenesis, and fatty acid oxidation. The authors also discussed the extensive post-translational modifications—including phosphorylation, acetylation, methylation, O-GlcNAcylation, and ubiquitination—that tightly regulate PGC-1α stability and coactivation efficiency. Finally, the review highlighted recent progress in identifying 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 challenges posed by the protein's structural disorder in drug discovery.

The review elucidated that PGC-1α acts as a master transcriptional coactivator, orchestrating cellular energy metabolism and mitochondrial biogenesis through dynamic interactions with transcription factors such as PPARs, ERRs, and NRFs. These complexes are critical for regulating processes like thermogenesis, gluconeogenesis, and fatty acid oxidation, which are essential for maintaining metabolic homeostasis. The authors emphasized that PGC-1α's diverse functional domains and three-dimensional structure facilitate these interactions.

Crucially, PGC-1α's activity and stability are tightly controlled by a diverse array of post-translational modifications including phosphorylation, acetylation, methylation, O-GlcNAcylation, and ubiquitination, each fine-tuning its coactivation efficiency and cellular localization. Furthermore, the review identified promising small molecule modulators, such as the activator ZLN005 and the inhibitor SR18292, which demonstrate physiological outcomes relevant to metabolic disorders and cancer. These findings underscore PGC-1α's central role in bioenergetic regulation and its potential as a therapeutic target, despite challenges posed by its structural disorder in drug discovery.