Mitochondrial estrogen receptor β inhibits cell apoptosis via interaction with Bad in a ligand-independent manner

Previous studies reported that estrogen receptor beta (ER beta) is localized to mitochondria, whereas little is known about the physiological functions of mitochondrial ER beta. In the present study, we explored the role of mitochondrial ER beta in regulating apoptosis using stable ER beta-expressing and ER beta knockdown cells lines. We found that exogenous ER beta was mainly expressed in mitochondrial but not in nuclear after ER beta overexpression and protected cells from apoptosis induced by hydrogen peroxide (H2O2), ultraviolet (UV), and staurosporine (STS). Moreover, overexpression of ER beta prevented Bax activation, cytochrome c release, caspase-3 activation, and PARP cleavage during apoptosis. Furthermore, knockdown of ER beta significantly suppressed the expression of ER beta in mitochondrial and promoted cell apoptosis induced by H2O2, UV, and STS. Downregulation of ER beta also enhanced Bax activation, cytochrome c release, caspase-3 activation and PARP cleavage. In addition, our study discovered that mitochondrial ER beta interacted with proapoptotic protein Bad in a ligand-independent manner, which suggests that mitochondrial ER beta inhibits Bad, and prevents Bax activation and cytochrome c release. Collectively, the results of this study support that mitochondrial ER beta prevents cell apoptosis via the mitochondrial apoptotic pathway in a ligand-independent manner.