Anti-Apoptotic and Antioxidant Activities of the Mitochondrial Estrogen Receptor Beta in N2A Neuroblastoma Cells

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 (mtER beta) 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 mtER beta 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 H2O2-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-beta estradiol (E2). Thus, the direct involvement of mtER beta in antioxidant and anti-apoptotic activities is documented, rendering mtER beta a promising therapeutic target for mitochondrial dysfunction-associated degenerative diseases.

Automated summary

Estrogens play a crucial role in regulating both reproductive and non-reproductive system physiology, with a particular impact on the nervous system. The presence of mitochondrial estrogen receptor beta (mtER beta) has been shown to directly participate in neuronal physiology maintenance. Overexpression of mtER beta in N2A cells enhances resistance to apoptotic stimuli, suggesting its potential as a therapeutic target for degenerative diseases associated with mitochondrial dysfunction.