Estradiol stimulates transcription of nuclear respiratory factor-1 and increases mitochondrial biogenesis.
Estrogen has direct and indirect effects on mitochondrial activity, but the mechanisms mediating these effects remain unclear. Others reported that long-term estradiol (E(2)) 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 E(2) 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 E(2) increased NRF-1 mRNA and protein in MCF-7 breast and H1793 lung adenocarcinoma cells in a time-dependent manner. E(2)-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 E(2) regulation of NRF-1 transcription. An estrogen response element (ERE) in the NRF-1 promoter bound ER alpha and ER beta in vitro, and E(2) induced ER alpha and ER beta 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 alpha and ER beta revealed that ER alpha mediates E(2)-induced NRF-1 transcription. The E(2)-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 E(2) stimulation of mitochondrial biogenesis and activity, indicating a mechanism by which estrogens regulate mitochondrial function by increasing NRF-1 expression.
Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, 580 South Preston Street, Louisville, Kentucky 40202, USA.
Kathleen A
KA
Mattingly
Margarita M
MM
Ivanova
Krista A
KA
Riggs
Nalinie S
NS
Wickramasinghe
Margaret J
MJ
Barch
Carolyn M
CM
Klinge
D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004272:DNA, Mitochondrial / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D000077267:Fulvestrant; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology; D051266:Nuclear Respiratory Factor 1 / Q000096:biosynthesis* / Q000235:genetics; D010636:Phenols; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology*
C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D024101:Mitochondrial Proteins; C495633:NRF1 protein, human; D009570:Nitriles; D051266:Nuclear Respiratory Factor 1; D010636:Phenols; D011422:Propionates; D011720:Pyrazoles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C499631:TFAM protein, human; D014157:Transcription Factors; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D000077267:Fulvestrant; D004958:Estradiol