Estrogen-related receptor alpha (ERR alpha) is an important mediator of mitochondrial biogenesis and function. To investigate the transcriptional network controlling these phenomena, we investigated mitochondrial gene expression in embryonic fibroblasts isolated from ERR alpha null mice. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) stimulated mitochondrial gene expression program in control cells, but not in the ERR alpha null cells. Interestingly, the induction Of levels of mitochondrial oxidative stress protection genes in response to increased PGC-1 alpha levels was dependent on ERR alpha. Furthermore, we found that the PGC-1 alpha-mediated induction of estrogen-related receptor gamma and nuclear respiratory factor 2 (NRF-2), was dependent on the presence of ERR alpha. Basal levels of NRF-2 were decreased in thic absence of ERR alpha. The absence of ERR alpha resulted in a decrease in citrate synthase enzyme activity ill response to PGC-1 alpha, overexpression. Our results indicate all essential role for ERRa as a key regulator of oxidative metabolism. (c) 2007 Elsevier Inc. All rights reserved.