Mitochondrial regulator PGC-1a-Modulating the modulator

Abstract

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a) is a central regulator of metabolism that is poised at the intersection of myriad intracellular signaling pathways. In this brief update, we discuss regulation of PGC-1a at multiple levels, including transcriptional, post-transcriptional, and post-translational modifications. We discuss recently identified small molecule effectors of PGC-1a that offer translational potential and promise new insight into PGC-1a biology. We highlight novel mechanistic insights relating to PGC-1a's interactions with RNA to enhance transcription and potentially influence transcript processing. Finally, we place these exciting new data in the context of aging biology, offering PGC-1a as a candidate target with terrific potential in anti-aging interventions.

Figure 1

PGC-1a protein structure and post-translational modifications. (a) Schematic of PGC-1a protein features: SR-rich domain, serine-arginine–rich domain; NLS, nuclear localization sequence; RRM, RNA-recognition motif; CBP80 binding domain. (b) FoldIndex prediction of folded and unfolded regions. PGC-1a, peroxisome proliferator–activated receptor gamma coactivator-1 alpha.

Figure 2

Signaling upstream of PGC-1a and general outcomes of PGC-1a activation. Red arrows indicate changes in PGC-1a activity or intracellular localization, and blue arrows indicate changes in protein stability. PGC-1a, peroxisome proliferator–activated receptor gamma coactivator-1 alpha.

Figure 3

Recent advances in PGC-1a biology. (a) Methylation of PGC-1a at residue K799. (b) SR-18292 inhibition of PGC-1a. (C, D) PGC-1a interaction with RNA. PGC-1a, peroxisome proliferator–activated receptor gamma coactivator-1 alpha.