Department of Biochemistry and Biotechnology, University of Thessaly, 81500 Larissa, Greece.
Int J Mol Sci. 2021 Jul 16;22(14):7620. doi: 10.3390/ijms22147620.
Estrogens are steroid hormones that play a crucial role in the regulation of the reproductive and non-reproductive system physiology. Among non-reproductive systems, the nervous system is mainly affected by estrogens due to their antioxidant, anti-apoptotic, and anti-inflammatory activities, which are mediated by membranous and nuclear estrogen receptors, and also by non-estrogen receptor-associated estrogen actions. Neuronal viability and functionality are also associated with the maintenance of mitochondrial functions. Recently, the localization of estrogen receptors, especially estrogen receptor beta, in the mitochondria of many types of neuronal cells is documented, indicating the direct involvement of the mitochondrial estrogen receptor beta (mtERβ) in the maintenance of neuronal physiology. In this study, cell lines of N2A cells stably overexpressing a mitochondrial-targeted estrogen receptor beta were generated and further analyzed to study the direct involvement of mtERβ in estrogen neuroprotective antioxidant and anti-apoptotic actions. Results from this study revealed that the presence of estrogen receptor beta in mitochondria render N2A cells more resistant to staurosporine- and HO-induced apoptotic stimuli, as indicated by the reduced activation of caspase-9 and -3, the increased cell viability, the increased ATP production, and the increased resistance to mitochondrial impairment in the presence or absence of 17-β estradiol (E2). Thus, the direct involvement of mtERβ in antioxidant and anti-apoptotic activities is documented, rendering mtERβ a promising therapeutic target for mitochondrial dysfunction-associated degenerative diseases.
雌激素是类固醇激素，在调节生殖和非生殖系统生理中起着至关重要的作用。在非生殖系统中，由于其抗氧化、抗凋亡和抗炎活性，神经系统主要受到雌激素的影响，这些活性是通过膜和核雌激素受体以及非雌激素受体相关的雌激素作用来介导的。神经元的存活和功能也与维持线粒体功能有关。最近，许多类型的神经元细胞中线粒体中雌激素受体，特别是雌激素受体β的定位被记录下来，表明线粒体雌激素受体β（mtERβ）直接参与维持神经元生理学。在这项研究中，生成了稳定过表达线粒体靶向雌激素受体β的 N2A 细胞系，并进一步进行了分析，以研究 mtERβ 在雌激素神经保护抗氧化和抗凋亡作用中的直接参与。这项研究的结果表明，线粒体中存在雌激素受体β使 N2A 细胞对 staurosporine 和 HO 诱导的凋亡刺激更具抗性，这表现在 caspase-9 和 -3 的激活减少、细胞活力增加、ATP 产生增加以及在存在或不存在 17-β 雌二醇（E2）的情况下对线粒体损伤的抵抗力增加。因此，mtERβ 直接参与抗氧化和抗凋亡活性，使其成为与线粒体功能障碍相关的退行性疾病的有前途的治疗靶点。
