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.

临床上已证明慢性压力与患者抑郁症的形成有关，并且已知激素可介导情绪障碍的某些临床表现。慢性束缚压力会引起啮齿动物大脑区域的形态重组，这种影响也伴随着行为变化。尽管这些作用背后的确切机制仍有待阐明，但越来越多的数据表明，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发挥重要作用。我们试图研究慢性应激期间激素调节的线粒体功能。 建立皮质神经元培养物以确定糖皮质激素受体在线粒体中的定位和功能。在培养的皮层神经元中用低浓度 (100 nM) 和高浓度 (1,000 nM) 皮质酮处理 1.5 小时后，糖皮质激素受体转移到线粒体中。与线粒体功能的增强一致，24 小时处理后，线粒体部分中线粒体编码的基因细胞色素氧化酶 I (COXI)（其启动子区域有 GRE）表达也有所增加。然而，治疗三天后，1uM 皮质酮会导致线粒体中 GR 水平下降，而 100nM 皮质酮治疗则不会。类似地，高浓度（1uM）和低浓度（100nM）皮质酮处理一天后，线粒体膜电位以相似的程度增强，与100nM皮质酮相比，仅高浓度（1uM）处理3天后，线粒体膜电位显着降低。此外，用高浓度（1uM）和低浓度（100nM）皮质酮处理一天后，线粒体氧化以相似的程度增强，并且与100nM皮质酮和未处理对照相比，仅高浓度（1uM）处理3天后线粒体膜电位显着降低。为了确定慢性应激下的情况，我们发现慢性应激后前额皮质组织线粒体部分中线粒体中的糖皮质激素受体水平显着降低，这表明在体外高浓度和长期皮质酮治疗后也出现类似的变化。这些研究可能为糖皮质激素调节线粒体功能和神经元信号传导的机制提供更多见解。此外，这项研究还有可能有助于更全面地了解慢性压力和激素调节细胞可塑性和恢复力的机制，并有助于未来改进疗法的发展。