The PGC-1 family of regulated coactivators (PGC-1alpha, PGC-1beta, and PRC) plays an important role in directing respiratory gene expression in response to environmental signals. Here, we show that PRC and PGC-1alpha differ in their interactions with nuclear hormone receptors but are highly similar in their direct binding to several nuclear transcription factors implicated in the expression of the respiratory chain. Surprisingly, neither coactivator binds NRF-2(GABP), a multisubunit transcriptional activator associated with the expression of many respiratory genes. However, the NRF-2 subunits and PRC are co-immunoprecipitated from cell extracts indicating that the two proteins exist in a complex in vivo. Several lines of evidence indicate that HCF-1 (host cell factor 1), a major chromatin component, mediates the association between PRC and NRF-2. Both PRC and NRF-2beta bind HCF-1 in vitro, and the molecular determinants required for the interactions of each with HCF-1 are also required for PRC trans-activation through promoter-bound NRF-2. These determinants include a consensus HCF-1 binding site on PRC and the NRF-2 activation domain. In addition, PRC and NRF-2beta can complex with HCF-1 in vivo, and all three associate with NRF-2-dependent nuclear genes that direct the expression of the mitochondrial transcription factors, TFB1M and TFB2M. Finally, short hairpin RNA-mediated knock down of PRC protein levels leads to reduced expression of TFB2M mRNA and mitochondrial transcripts for cytochrome oxidase II (COXII) and cytochrome b. These changes in gene expression coincide with a marked reduction in cytochrome oxidase activity. The results are consistent with a pathway whereby PRC regulates NRF-2-dependent genes through a multiprotein complex involving HCF-1.