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Estrogen-related receptor alpha (ERRalpha) 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 ERRalpha null mice. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) stimulated mitochondrial gene expression program in control cells, but not in the ERRalpha null cells. Interestingly, the induction of levels of mitochondrial oxidative stress protection genes in response to increased PGC-1alpha levels was dependent on ERRalpha. Furthermore, we found that the PGC-1alpha-mediated induction of estrogen-related receptor gamma and nuclear respiratory factor 2 (NRF-2), was dependent on the presence of ERRalpha. Basal levels of NRF-2 were decreased in the absence of ERRalpha. The absence of ERRalpha resulted in a decrease in citrate synthase enzyme activity in response to PGC-1alpha overexpression. Our results indicate an essential role for ERRalpha as a key regulator of oxidative metabolism.

Non-invasive imaging of gene expression opens new prospects for the study of transgenic animals and the implementation of genetically based therapies in patients. We have sought to establish a general paradigm to enable whole body non-invasive imaging of any transgene. We show that the expression and imaging of HSV1-tk (a marker gene) can be used to monitor the expression of the LacZ gene (a second gene) under the transcriptional control of a single promoter within a bicistronic unit that includes a type II internal ribosomal entry site. In cells bearing a single copy of the vector, the expression of the two genes is proportional and constant, both in vitro and in vivo. We demonstrate that non-invasive imaging of HSV1-tk gene accurately reflects the topology and activity of the other cis-linked transgene.