Regulation of nuclear respiratory factor-1 expression by 17beta-estradiol : a new mechanism for coordinating mitochondrial gene expression.

The mechanisms by which estrogens regulate mitochondrial activity are not completely understood. Chronic treatment of ovariectomized rats with estradiol (E 2 ) increased the amount of Nuclear Respiratory Factor-1 (NRF-1) protein in cerebral blood vessels. NRF-1 is a transcription factor that regulates the expression of nuclear-encoded mitochondrial genes including mitochondrial transcription factor A ( TFAM , which, in turn, controls transcription of the mitochondrial genome. Here, I tested the hypothesis that E 2 increases NRF-1 transcription through a genomic activation of estrogen receptor (ER) resulting in a coordinate increase in nuclear- and mitochondrial- encoded genes, mitochondrial respiratory activity, and mitochondrial biogenesis. E 2 increased NRF-1 mRNA and protein in MCF-7 breast and H1793 lung adenocarcinoma cells in a time-, concentration-, and ER-dependent manner. E 2 -induced NRF-1 expression was inhibited by Actinomycin D, but not by inhibitors of the PI3K or MAPK pathways, indicating a genomic mechanism of E 2 action. An estrogen response element in the NRF-1 promoter bound ERá and Erâ in vitro and in chromatin immunoprecipitation assays in MCF-7 cells and activated reporter gene expression in transfected cells. The E 2 -induced increase in NRF-1 was followed in time by increased TFAM Tfam-regulated, mtDNA-encoded COI and NDI , and mitochondrial biogenesis. The selective ER modulators (SERMs) 4-hydroxytramoxifen (4-OHT) and raloxifene (RAL) also increased NRF-1 expression by a mechanism involving ER nongenomic and genomic activities. E 2 , 4-OHT, and RAL also increased NRF-1 expression in Human Umbilical Vein Endothelial Cells (HUVEC) by a genomic ER mechanism. Exposure to Diesel Exhaust Particle Extracts (DEPE) may promote vascular disease and DEPE are antagonists of genomic estrogen responses. DEPE suppressed the basal expression of NRF-1 in HUVEC and ablated the stimulatory effect of E 2 , 4-OHT, and RAL on NRF-1 transcription. Lastly, a known cardioprotective phytoestrogen, resveratrol, stimulated NRF-1 expression in HUVEC and inhibited the ability of DEPE to suppress basal NRF-1. In summary, the research presented here characterizes a possibly important ER-mediated pathway to account for the observed beneficial effects of E 2 on mitochondrial function. These results suggest that administration of E 2 or SERMs may be beneficial in treating pathological conditions involving mitochondrial dysfunction including heart disease, neurodegenerative disorders, and cancer