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Estradiol Stimulates Transcription of Nuclear Respiratory Factor-1 and Increases Mitochondrial Biogenesis

Department of Biochemistry and Molecular Biology (K.A.M., M.M.I., K.A.R., N.S.W., C.M.K.), Center for Genetics and Molecular Medicine, and Department of Pediatrics (M.J.B.), Cytogenetics Lab, University of Louisville School of Medicine, Louisville, Kentucky 40292

Address all correspondence and requests for reprints to: Carolyn M. Klinge, Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, 580 South Preston Street, Louisville, Kentucky 40202. E-mail: carolyn.klinge{at}louisville.edu.

Estrogen has direct and indirect effects on mitochondrial activity, but the mechanisms mediating these effects remain unclear. Others reported that long-term estradiol (E₂) treatment increased nuclear respiratory factor-1 (NRF-1) protein in cerebral blood vessels of ovariectomized rats. NRF-1 is a transcription factor that regulates the expression of nuclear-encoded mitochondrial genes, e.g. mitochondrial transcription factor A (TFAM), that control transcription of the mitochondrial genome. Here we tested the hypothesis that E₂ increases NRF-1 transcription resulting in a coordinate increase in the expression of nuclear- and mitochondrial- encoded genes and mitochondrial respiratory activity. We show that E₂ increased NRF-1 mRNA and protein in MCF-7 breast and H1793 lung adenocarcinoma cells in a time-dependent manner. E₂-induced NRF-1 expression was inhibited by the estrogen receptor (ER) antagonist ICI 182,780 and actinomycin D but not by phosphoinositide-3 kinase and MAPK inhibitors, indicating a genomic mechanism of E₂ regulation of NRF-1 transcription. An estrogen response element (ERE) in the NRF-1 promoter bound ER and ERβ in vitro, and E₂ induced ER and ERβ recruitment to this ERE in chromatin immunoprecipitation assays in MCF-7 cells. The NRF-1 ERE activated reporter gene expression in transfected cells. Small interfering RNA to ER and ERβ revealed that ER mediates E₂-induced NRF-1 transcription. The E₂-induced increase in NRF-1 was followed by increased TFAM and the transcription of Tfam-regulated mitochondrial DNA-encoded COI and NDI genes and increased mitochondrial biogenesis. Knockdown of NRF-1 blocked E₂ stimulation of mitochondrial biogenesis and activity, indicating a mechanism by which estrogens regulate mitochondrial function by increasing NRF-1 expression.

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Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen  |  Fulvestrant