**4.1 Regulation via binding with co-activator PGC-1**

Like other NRs, ERRs bind to co-activators for their functions. Although the p160 family of coactivator SRC-1 was used to co-crystalize with LBD of ERRγ, the p160 family of coactivators only weakly bind with ERRs. On the other hand, ERRα is identified as one of the primary partner for PGC-1α in the regulation of mitochondrial biogenesis [56]. PGC-1 was discovered to bind both ERRα and γ via a LXXLL motif that is also necessary for PGC-1 to bind other nuclear receptors [57]. The AF-2 domains on ERRs are needed for this binding to occur. PGC-1 is highly expressed in tissues with high energy demands including heart, kidney, brown fat, and muscle [58], similar to the tissue distribution of ERRα and γ. Studies suggest that PGC-1 can be considered as the protein "ligand" for ERR since there is no endogenous lipophilic ligand identified for ERRs [59]. Binding to PGC-1α turns ERRα from a weak to a strong transcriptional factor. This is achieved by directly increasing of ERRα expression as PGC-1α-ERRα complex binds to the promoters of ERRα itself [60, 61]. In addition, cofactor binding allows ERRs to assume active conformation and increase its activity as a transcriptional factor [16, 62]. Together, the PGC-1α-ERR complex activates genes that encode proteins critical for mitochondrial components or activating transcription factors involved in mitochondrial biogenesis. In addition, PGC-1β, another isoform of PGC-1 coactivators that is often considered regulators of basal mitochondrial biogenesis, has also been reported to bind and regulate the transcriptional activities of ERRs.
