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Mitochondrial localization of ER and ER in human MCF7 cells

¹Division of Toxicological Sciences, Department of Environmental Health Sciences, Bloomberg School of Public Health and ²Microscopy Facility, Johns Hopkins School of Medicine, Baltimore, Maryland 21205

Submitted 11 November 2003 ; accepted in final form 20 January 2004

We observed previously that estrogen treatment increased the transcript levels of several mitochondrial DNA (mtDNA)-encoded genes for mitochondrial respiratory chain (MRC) proteins and MRC activity in rat hepatocytes and human Hep G2 cells. Others have reported detection of estrogen receptors (ER), ER and ER, in mitochondria of rabbit ovarian and uterine tissue. In this study, we have extended these observations. Using cellular fractionation and Western blot with ER- and ER-specific antibodies, we observed that ER and ER are present in mitochondria of human MCF7 cells and that the mitochondrial ER and ER account for 10 and 18%, respectively, of total cellular ER and ER in 17-estradiol (E₂)-treated MCF7 cells. We also found that E₂ significantly enhanced the amounts of mitochondrial ER and ER in a time- and concentration-dependent manner and that these effects are accompanied by a significant increase in the transcript levels of mtDNA-encoded genes, i.e., cytochrome c oxidase subunits I and II. Moreover, we demonstrated that these E₂-mediated effects were inhibited by the pure ER antagonist, ICI-182780, indicating the involvement of ERs. Using immunohistochemistry with confocal microscopy and immunogold electron microscopy, we demonstrated that ER and ER are located within the MCF7 cell mitochondrial matrix. Computer analysis identified a putative internal mitochondrial targeting peptide signal within human ER, suggesting an inherent potential for ER to enter mitochondria. These findings confirm the observations of others and provide additional support for this novel localization of the ERs and for a potentially important role of the ER in the regulation of mtDNA transcription.

17-estradiol; mitochondrial deoxyribonucleic acid transcription; mitochondrial deoxyribonucleic acid-encoded genes

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