Adzic Miroslav, Mitic Milos, Radojcic Marija
Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia.
Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia.
Brain Res. 2017 Sep 15;1671:77-84. doi: 10.1016/j.brainres.2017.07.007. Epub 2017 Jul 14.
Depression is a disease of an abnormal brain energy metabolism also marked with increased apoptosis in specific brain regions. Mounting evidence indicates that the mitochondrial oxidative phosphorylation and apoptosis are novel targets for the actions of estrogen receptors (ERs). In this study, we examined the effects of antidepressant (AD) fluoxetine (FLU) treatment on the mitochondrial ER alpha (ERα), ER beta (total and phospho-pERβ) and their association with cytochrome c (cyt c) oxidase activity and apoptotic Bcl2/Bax-molecules in the hippocampal mitochondria of chronically isolated (CPSI) female and male rats depicting depression. Impaired behaviour induced by CPSI was followed by decreased corticosterone (CORT) in both sexes and downregulation of cyt c oxidase in males. CPSI did not affect the ERα in either of sexes, but it decreased mitochondrial ERβ and increased pERβ in both sexes. Stress-reduced ERβ is associated with a decrease in mitochondrial energetic processes in males and with apoptotic mechanisms in females. FLU normalized behaviour in both sexes and increased cyt c oxidase in females. FLU elevated ERα in males, increased ERβ and decreased pERβ in both sexes. The AD-induced alterations of ERβ paralleled with bioenergetics and pro-survival pathways in females. In conclusion, sex-unspecific regulation of ERβ by the stress and by AD and its differential convergence with bioenergetics and apoptotic pathways in females and males implies its role as a vulnerability factor in the stress response and emphasizes mitochondrial ERβ-dependent pathways as an important gateway of ADs action, at least in females.
抑郁症是一种大脑能量代谢异常的疾病，其特征还包括特定脑区凋亡增加。越来越多的证据表明，线粒体氧化磷酸化和凋亡是雌激素受体（ERs）作用的新靶点。在本研究中，我们检测了抗抑郁药（AD）氟西汀（FLU）治疗对长期隔离（CPSI）的抑郁模型雌性和雄性大鼠海马线粒体中ERα、ERβ（总量和磷酸化pERβ）及其与细胞色素c（cyt c）氧化酶活性和凋亡相关Bcl2/Bax分子的关联的影响。CPSI诱导的行为障碍在两性中均伴有皮质酮（CORT）降低，在雄性中伴有细胞色素c氧化酶下调。CPSI对两性的ERα均无影响，但降低了两性的线粒体ERβ并增加了pERβ。应激导致的ERβ降低在雄性中与线粒体能量代谢过程减少相关，在雌性中与凋亡机制相关。FLU使两性行为恢复正常，并增加了雌性的细胞色素c氧化酶。FLU使雄性的ERα升高，使两性的ERβ增加并使pERβ降低。AD诱导的ERβ改变与雌性的生物能量学和促生存途径平行。总之，应激和AD对ERβ的性别非特异性调节及其在雌性和雄性中与生物能量学和凋亡途径的差异趋同表明其作为应激反应中易感性因素的作用，并强调线粒体ERβ依赖性途径作为AD作用的重要通道，至少在雌性中如此。
