Estrogen's Effects on Mitochondrial Gene Expression: Mechanisms and Potential Contributions to Estrogen Carcinogenesis

Abstract

Estrogen receptor (ER)alpha and ERbeta are localized in the nucleus and involved in the regulation of nuclear estrogen-responsive genes by 17beta estradiol (E2). In addition, recently others have shown that upon E2 binding, ERalpha localizes to the plasma membrane and initiates mitogen-activated protein kinase (MAPK)-mediated signal transduction. Previously, we reported that in liver, cultured rat hepatocytes and human HepG2 cells, estrogen treatment enhanced mitochondrial DNA (mtDNA)-encoded gene transcript levels. These effects were blocked by a specific antiestrogen, suggesting a role for the ER. Others have reported the presence of putative estrogen-responsive elements in mtDNA. These observations suggested the hypothesis that the ER localized in mitochondria and functioned directly to enhance the levels of mtDNA-encoded transcripts, analogous to what has been observed for the glucocorticoid hormone receptor. Using Western blot analysis, confocal immunofluorescence, immunogold electron microscopy, and gel electrophoresis mobility shift assays, we have demonstrated the estrogen-dependent presence of ERbeta and ERalpha within mitochondria of HepG2 and MCF-7 human breast tumor cells. Together, these results suggest that the ERs may act as transcription factors directly involved in the regulation by E2 of mtDNA transcription.

Evaluation of sex differences on mitochondrial bioenergetics and apoptosis in mice

“…Another possible alternative to explain the gender-specific modulation of ROS production is a direct regulation of mitochondrial genome by estrogens (Chen and Yager, 2004). In fact, the estrogen receptor is present in mitochondria (Grossman et al, 1989 Although estrogens can be responsible for the lower mitochondrial ROS production and longer life span of females in rat strains, why don't they have the same effect in mice?…”

Role of receptor complexes in the extranuclear actions of estrogen receptor α in breast cancer

“…Whether ERa membrane translocation and its activation on the cell membrane are sequential or an independent event is not presently known. We also do not understand the biological role of cytosol ERa in E2 rapid action, although effects on the mitochondria have been reported (Chen & Yager 2004). …”

Estrogens and Brain

“…Хроническое накопление активных форм кислорода, которое ведет к инактивации ключевых ферментов и накоплению мутаций митохондриальной ДНК, рассматривается как возможный патогенетический механизм развития возраст-ассоциированных заболе-ваний ЦНС [59]. В мембранах митохондрий определены оба типа РЭ, при этом митохондриальная ДНК имеет палиндром ЭЧЭ [60], поэтому митохондрии являются полноценной мишенью действия эстрогенов. Защитное действие эстрогена на митохондрии включает: влияние на митохондриальную жизнеспособность и функциони-рование, апоптоз и гомеостаз кальция.…”