Estradiol and tamoxifen regulate NRF-1 and mitochondrial function in mouse mammary gland and uterus

Nuclear respiratory factor-1 (NRF-1) stimulates the transcription of nuclear-encoded genes that regulate mitochondrial (mt) genome transcription and biogenesis. We reported that estradiol (E-2) and 4-hydroxytamoxifen (4-OHT) stimulate NRF-1 transcription in an estrogen receptor a (ER alpha)- and ERb-dependent manner in human breast cancer cells. The aim of this study was to determine whether E-2 and 4-OHT increase NRF-1 in vivo. Here, we report that E-2 and 4-OHT increase NRF-1 expression in mammary gland (MG) and uterus of ovariectomized C57BL/6 mice in a time-dependent manner. E-2 increased NRF-1 protein in the uterus and MG; however, in MG, 4-OHT increased Nrf1 mRNA but not protein. Chromatin immunoprecipitation assays revealed increased in vivo recruitment of ER alpha to the Nrf1 promoter and intron 3 in MG and uterus 6 h after E-2 and 4-OHT treatment, commensurate with increased NRF-1 expression. E-2- and 4-OHT-induced increases in NRF-1 and its target genes Tfam, Tfb1m, and Tfb2m were coordinated in MG but not in uterus due to uterine-selective inhibition of the expression of the NRF-1 coactivators Ppargc1a and Ppargc1b by E-2 and 4-OHT. E-2 transiently increased NRF-1 and PGC-1 alpha nuclear staining while reducing PGC-1 alpha in uterus. E-2, not 4-OHT, activates mt biogenesis in MG and uterus in a time-dependent manner. E-2 increased mt outer membrane Tomm40 protein levels in MG and uterus whereas 4-OHT increased Tomm40 only in uterus. These data support the hypothesis of tissue-selective regulation of NRF-1 and its downstream targets by E-2 and 4-OHT in vivo.