Glucocorticoid Receptors (GR) in Mitochondria: The Role

糖皮质激素受体 (GR) 在线粒体中的作用

• 批准号: 7312914
• 负责人: HUSSEINI K MANJI
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7312914
• 关键词: Glucocorticoid; Receptors; GR; Mitochondria; Role

Chronic stress has been shown to be associated clinically with formation of depression in patients and hormones are known to mediate certain clinical manifestations of mood disorders. Chronic restraint stress induces a morphological reorganization in the areas of rodent brain, effects which are also accompanied by behavioral changes. Although the precise mechanisms underlying these effects remain to be elucidated, increasing data suggests that an alteration in neuroprotection and mitochondrial functions may play an important role in regulating various forms of synaptic and neural plasticity; we have sought to investigate the mitochondrial functions regulated by hormones during chronic stress. Cortical neuronal cultures were established in order to determine the localization and function of glucocorticoid receptors in the mitochondria. Glucocorticoid receptors translocated into mitochondria after 1.5 hour treatment with low concentration (100 nM) and high concentration (1,000 nM) of corticosterone in cultured cortical neurons. Consistent with the enhancement of mitochondrial function, mitochondrially encoded gene cytochrome oxidase I (COXI) (has GRE in its promoter region) expression was also increased in mitochondria fraction after 24 hours treatment. However, after three days of treatment, 1uM corticosterone resulted in a decrease in GR levels in mitochondria and 100nM corticosterone treatment did not. Similarly, mitochondrial membrane potential were enhanced after one day treatment with high (1uM) and low (100nM) concentration of corticosterone in a similar extend, and only high concentration (1uM) significantly decreased in mitochondrial membrane potential after 3 day treatment in comparison to the 100nM corticosterone. In addition, mitochondrial oxidation were enhanced after one day treatment with high (1uM) and low (100nM) concentration of corticosterone in a similar extend, and only high concentration (1uM) significantly decreased in mitochondrial membrane potential after 3 day treatment in comparison to the 100nM corticosterone and untreated control. To determine the situation under chronic stress, we found that glucocorticoid receptor levels in mitochondria were significantly decreased in the mitochondrial fraction from prefrontal cortex tissue after chronic stress, suggesting a similar change after high concentration and long-term corticosterone treatment in vitro. These studies may provide additional insights into the mechanisms by which glucocorticoid regulate mitochondrial function and neuronal signaling. Furthermore, this research also has the potential to contribute to a more complete understanding of the mechanisms by which chronic stress and hormones regulate cellular plasticity and resilience and to the future development of improved therapeutics.

慢性应激已被证明与患者的抑郁形成有关，众所周知，激素可以介导某些情绪障碍的临床表现。慢性约束应力诱导啮齿动物大脑区域的形态重组，其作用也伴随着行为改变。尽管这些作用的基本机制尚待阐明，但增加的数据表明，神经保护和线粒体功能的改变可能在调节各种形式的突触和神经可塑性方面起重要作用。我们试图研究慢性应激期间由激素调节的线粒体功能。 建立了皮质神经元培养物，以确定线粒体中糖皮质激素受体的定位和功能。糖皮质激素受体在培养的皮质神经元中以低浓度（100 nm）和高浓度（1,000 nm）的高浓度（1,000 nm）治疗后，在线粒体中转移到线粒体中。与线粒体功能的增强，线粒体编码的基因细胞色素氧化酶I（COXI）（COXI）（在其启动子区域中具有GRE）的表达在24小时后的线粒体分数中也增加了。但是，经过三天的治疗，1UM皮质酮导致线粒体和100nm皮质酮治疗的GR水平降低。类似地，一日治疗在类似延伸的高（1UM）和低（100nm）浓度的皮质酮浓度后，线粒体膜电位得到增强，仅在3天治疗后与100nm corticosterone相比，线粒体膜电位的高浓度（1UM）显着降低。另外，在类似延伸的一日治疗后，用高（1UM）和低（100nm）浓度的皮质酮浓度来增强线粒体氧化，仅在3天治疗后，仅在三天治疗后与100nm corticosterone和未经处理的对照相比，仅在三天治疗后，高浓度（1UM）显着降低了高浓度（1UM）。为了确定慢性应激下的情况，我们发现线粒体中线粒体中线粒体中的糖皮质激素受体水平在慢性应激后从前额叶皮层组织中显着降低，这表明高浓度和长期皮质激素治疗后在体外情况下发生了类似的变化。这些研究可能会提供有关糖皮质激素调节线粒体功能和神经元信号传导的机制的更多见解。此外，这项研究还有可能有助于更完整地了解慢性应激和激素调节细胞可塑性和弹性的机制，以及改善治疗剂的未来发展。