The hitchhiker's guide to PGC-1α isoform structure and biological functions

Proteins of the peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator 1 (PGC-1) family of transcriptional coactivators coordinate physiological adaptations in many tissues, usually in response to demands for higher nutrient and energy supply. Of the founding members of the family, PGC-1 alpha (also known as PPARGC1A) is the most highly regulated gene, using multiple promoters and alternative splicing to produce a growing number of coactivator variants. PGC-1 alpha promoters are selectively active in distinct tissues in response to specific stimuli. To date, more than ten novel PGC-1 alpha isoforms have been reported to be expressed from a novel promoter (PGC-1 alpha-b, PGC-1 alpha-c), to undergo alternative splicing (NT-PGC-1 alpha) or both (PGC-1 alpha 2, PGC-1 alpha 3, PGC-1 alpha 4). The resulting proteins display differential regulation and tissue distribution and, most importantly, exert specific biological functions. In this review we discuss the structural and functional characteristics of the novel PGC-1 alpha isoforms, aiming to provide an integrative view of this constantly expanding system of transcriptional coactivators.