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

Abstract

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 F actor-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 (TF AM), which, in tum, controls transcription of the mitochondrial genome. Here, I tested the hypothesis that E2 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. E2 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 E2 action. An estrogen response element in the NRF -1 promoter bound ERa and ERP 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 lV CO! and ND!; and mitochondrial biogenesis. The selective ER modulators (SERMs) 4-hydroxytramoxifen (4-0HT) and raloxifene (RAL) also increased NRF-1 expression by a mechanism involving ER nongenomic and genomic activities. E 2 , 4-0HT, 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 ofNRF-1 in HUVEC and ablated the stimulatory effect ofE 2 , 4-0HT, and RAL on NRF-1 transcription. Lastly, a known cardioprotective phytoestrogen, resveratrol, stimulated NRF -1 expression in HUVEC and inhibited the ability ofDEPE to suppress basal NRF-l. In summary, the research presented here characterizes a possibly important ER-mediated pathway to account for the observed beneficial effects of E2 on mitochondrial function. These results suggest that administration of E2 or SERMs may be beneficial in treating pathological conditions involving mitochondrial dysfunction including heart disease, neurodegenerative disorders, and cancer.