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.

慢性压力在临床上与患者抑郁症的形成有关，并且已知激素介导情绪障碍的某些临床表现。慢性束缚应激诱导啮齿类动物大脑区域的形态重组，其影响也伴随着行为变化。虽然这些影响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线粒体中糖皮质激素受体的定位和功能。在培养的皮质神经元中，用低浓度（100 nM）和高浓度（1，000 nM）皮质酮处理1.5小时后，糖皮质激素受体易位到线粒体中。与线粒体功能的增强一致，在处理24小时后，线粒体部分中的线粒体编码基因细胞色素氧化酶I（COXI）（在其启动子区具有GRE）表达也增加。然而，在处理三天后，1 μ M皮质酮导致线粒体中GR水平降低，而100 nM皮质酮处理则没有。同样，高浓度（1 μ M）和低浓度（100 nM）皮质酮处理1天后，线粒体膜电位以相似程度增强，与100 nM皮质酮相比，仅高浓度（1 μ M）处理3天后线粒体膜电位显著降低。此外，高浓度（1 μ M）和低浓度（100 nM）皮质酮处理1天后，线粒体氧化增强程度相似，与100 nM皮质酮和未处理对照相比，仅高浓度（1 μ M）处理3天后线粒体膜电位显著降低。为了确定在慢性应激下的情况，我们发现，糖皮质激素受体水平在线粒体中显着下降，在线粒体组分从前额叶皮层组织慢性应激后，表明类似的变化后，高浓度和长期的皮质酮在体外治疗。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额外的见解。此外，这项研究也有可能有助于更全面地了解慢性应激和激素调节细胞可塑性和弹性的机制，以及未来改进治疗方法的发展。