The estrogen-related receptor [alpha] (ERR[alpha]) functions in PPAR[gamma] coactivator 1[alpha] (PGC-1[alpha])-induced mitochondrial biogenesis

Estrogen-related receptor [alpha](ERR[alpha]) is one of the first orphan nuclear receptors to be identified, yet its physiological functions are still unclear. We show here that ERR[alpha] is an effector of the transcriptional coactivator PGC-1[alpha][peroxisome proliferator-activated receptor [gamma] (PPAR[gamma]) coactivator 1[alpha]], and that it regulates the expression of genes involved in oxidative phosphorylation and mitochondrial biogenesis. Inhibition of ERR[alpha] compromises the ability of PGC-1[alpha] to induce the expression of genes encoding mitochondrial proteins and to increase mitochondrial DNA content. A constitutively active form of ERR[alpha] is sufficient to elicit both responses. ERR[alpha] binding sites are present in the transcriptional control regions of ERR[alpha]/PGC-1[alpha]-induced genes and contribute to the transcriptional response to PGC-1[alpha]. The ERR[alpha]-regulated genes described here have been reported to be expressed at reduced levels in humans that are insulin-resistant. Thus, changes in ERR[alpha] activity could be linked to pathological changes in metabolic disease, such as diabetes.