Structure and function relationships in the PGC-1 family of transcriptional coactivators

Sammanfattning: PGC-1 coactivators are central regulators of several cellular processes, most notably the coupling between energy demands and supply. PGCs activate distinct biological processes in a tissue-specific manner. These include mitochondrial biogenesis, oxidative phosphorylation, oxygen transport, gluconeogenesis, angiogenesis, and muscle fiber-type specification. The family consists of three members: PGC-1α, PGC-1β, and PRC, among which the most studied is PGC-1α. Transcription of a single PGC-1α gene produces different isoforms (e.g. PGC-1α1 to α4) with different biological functions. All of the PGC- 1α isoforms share some domain similarity but PGC-1α2, α3 and α4 lack the C-terminal domains present in PGC-1α1. The actions of PGC-1α1 are strongly linked to energy metabolism, whereas PGC-1α4 regulates skeletal muscle hypertrophy. The functions of PGC-1α2 and PGC-1α3 have remained unknown. To study the mechanism of action of the new PGC-1α isoforms, we performed a protein complex purification and identified protein partners of all PGC-1α variants. We found that all PGC-1α isoforms can function as positive regulators of transcription by associating with members of the Mediator complex, histone acetyltransferase complexes, and splicing factors. Furthermore, we identified several transcription factors associated with each PGC- 1α isoform, which allowed us to predict how different target genes are regulated. Interestingly, we also observed that PGC-1α isoforms can regulate splicing events and can affect the exon composition of their corresponding target transcripts. Here, we report for the first time that PGC-1α1 can dimerize with other PGC-1α isoforms, suggesting that some of the functions of PGC-1α might be mediated by heterodimers. Since PGC-1α1 is a key modulator of cellular metabolism in several tissues, it has gained considerable attention as potential target for the treatment of metabolic disorders. For that reason, we developed a screening platform to identify chemicals that can induce PGC-1α1 protein accumulation. From this screen, we identified several candidate small molecules as potential PGC-1α1 activators, which were validated in brown adipocytes. We identified 4 compounds that can increase PGC-1α1 protein accumulation, target gene expression, and mitochondrial respiration. These compounds could represent the beginning of a new class of therapeutics against obesity and related disorders.