Estrogen Receptor β as a Mitochondrial Vulnerability Factor

Shao-Hua Yang,Saumyendra N Sarkar,Ran Liu,Evelyn J Perez,Xiaofei Wang,Yi Wen,Liang-Jun Yan,James W Simpkins

doi:10.1074/jbc.m808246200

Shao-Hua Yang, Saumyendra N Sarkar + Show 6 more

Open Access

https://doi.org/10.1074/jbc.m808246200

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Abstract

We recently demonstrated mitochondrial localization of estrogen receptor beta (ERbeta). We herein confirm the mitochondrial localization of ERbeta by the loss of mitochondrial ERbeta immunoreactivity in ERbeta knockdown cells. A phenotype change characterized as an increase in resistance to oxidative stressors is associated with ERbeta knockdown. ERbeta knockdown results in a lower resting mitochondrial membrane potential (Deltapsim) and increase in resistance to hydrogen peroxide-induced Deltapsim depolarization in both immortal hippocampal cells and primary hippocampal neurons. ERbeta knockdown cells maintained ATP concentrations despite insults that compromise ATP production and produce less mitochondrial superoxide under oxidative stress. Furthermore, similar mitochondrial phenotype changes were identified in primary hippocampal neurons derived from ERbeta knock-out mice. These data demonstrate that ERbeta is expressed in mitochondria and function as a mitochondrial vulnerability factor involved in Deltapsim maintenance, potentially through a mitochondrial transcription dependent mechanism.

Highlights

We and several other laboratories have recently reported the localization of ER␤ in mitochondria in various cells, including rat primary neurons [15, 18, 29], rat primary cardiomyocytes [15], a murine hippocampal cell line (HT-22), neurons and glia in rat hippocampus [13, 14], human breast cancer cell lines (MCF-7 and MCF10F) [16, 18], immortal human breast epithelial cells [18], human lens epithelial cell lines [17, 30], human osteosarcoma cells (SaOS-2) [31], hepatocarcinoma cells (HepG2) [31], and human sperm [32]
We demonstrate that ER␤ regulates a variety of mitochondrial functions, using a murine hippocampal cell line (HT-22) with permanent knockdown of ER␤ by RNA interference and primary hippocampal neurons derived from ER␤ knock-out mice
Knockdown of ER␤ by RNA Interference in HT-22 Cells—In order to investigate the role of ER␤, we established two permanent siER␤

Summary

Introduction

Increasing evidence has demonstrated that ER␤, while expressed in nuclei of some cell types, is mainly localized extranuclearly (14 –18). It became clear, not long after its identification, that ER␤ has biological roles distinct from those of ER␣ [9]. The localization of ER␤ in mitochondria suggests that ER␤ may function as a mitochondrial component. We demonstrate that ER␤ regulates a variety of mitochondrial functions, using a murine hippocampal cell line (HT-22) with permanent knockdown of ER␤ by RNA interference (siRNA) and primary hippocampal neurons derived from ER␤ knock-out mice

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