Bag-1 mediates glucocorticoid receptor trafficking to mitochondria after corticosterone stimulation: Potential role in regulating affective resilience,Journal of Neurochemistry

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Bag-1 mediates glucocorticoid receptor trafficking to mitochondria after corticosterone stimulation: Potential role in regulating affective resilience
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2020-10-07 , DOI: 10.1111/jnc.15211
Shaolei Luo ₁ , Yangyang Hou ₁ , Yaping Zhang ₁ , Lei Feng ₂ , Richard G Hunter ₃ , Peixiong Yuan ₄ , Yue Jia ₁ , Haoran Li ₁ , Gang Wang ₂ , Husseini K Manji ₅ , Bruce S McEwen ₆ , Chunjie Xiao ₁ , Hongkun Bao ₁ , Jing Du _{1,

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Affiliation

Molecular abnormalities within the Glucocorticoid Receptor (GR) stress signaling pathway involved in dysfunction of mitochondria and confer vulnerability to stress-related psychiatric disorders. Bcl-2 associated athanogene (Bag-1) is a target for the actions of mood stabilizers. Bag-1 interacts with GR, thereby regulating glucocorticoid function. In this study, we investigate the potential role of Bag-1 in regulating GR translocation into mitochondria. Corticosterone (CORT) treatment significantly enhanced Bag-1/GR complex formation and GR mitochondrial translocation in cultured rat cortical neurons after treatment for 30 min and 24 hr. By contrast, after stimulation with CORT for 3 days, localization of the Bag-1/GR complex and mitochondrial GR were reduced. Similar results were obtained in mice, in which administrated CORT in drinking water for 21 days significantly impaired the GR levels in the mitochondria, while Bag-1 over-expression rescued this reduction. Furthermore, chronic CORT exposure led to anhedonia-like and depression-like behaviors in the sucrose-consumption test and forced swimming test, and these behaviors were rescued by Bag-1 over-expression. These results suggest that Bag-1 mediates GR trafficking to mitochondria and regulates affective resilience in response to a CORT increase and provide potential insight into the mechanisms by which Bag-1 and GR could contribute to the physiology and pathogenesis of psychiatric disorders in response to the change of stress hormone.

中文翻译：

Bag-1 在皮质酮刺激后介导糖皮质激素受体向线粒体转运：在调节情感弹性中的潜在作用

糖皮质激素受体 (GR) 应激信号通路中的分子异常与线粒体功能障碍有关，并导致易患与应激相关的精神疾病。Bcl-2 相关的 athanogene (Bag-1) 是情绪稳定剂作用的目标。Bag-1 与 GR 相互作用，从而调节糖皮质激素功能。在这项研究中，我们研究了 Bag-1 在调节 GR 易位到线粒体中的潜在作用。在处理 30 分钟和 24 小时后，皮质酮 (CORT) 处理显着增强了培养的大鼠皮质神经元中 Bag-1/GR 复合物的形成和 GR 线粒体易位。相比之下，在用 CORT 刺激 3 天后，Bag-1/GR 复合物和线粒体 GR 的定位减少。在小鼠身上也得到了类似的结果，其中在饮用水中施用 CORT 21 天显着损害了线粒体中的 GR 水平，而 Bag-1 过表达挽救了这种减少。此外，慢性 CORT 暴露导致蔗糖消耗试验和强迫游泳试验中的快感缺乏样和抑郁样行为，这些行为被 Bag-1 过度表达所挽救。这些结果表明，Bag-1 介导 GR 运输到线粒体并调节响应 CORT 增加的情感弹性，并提供了对 Bag-1 和 GR 可能有助于精神疾病生理学和发病机制以响应压力荷尔蒙的变化。慢性 CORT 暴露导致蔗糖消耗试验和强迫游泳试验中的快感缺乏样和抑郁样行为，这些行为被 Bag-1 过度表达所挽救。这些结果表明，Bag-1 介导 GR 运输到线粒体并调节响应 CORT 增加的情感弹性，并提供了对 Bag-1 和 GR 可能有助于精神疾病生理学和发病机制以响应压力荷尔蒙的变化。慢性 CORT 暴露导致蔗糖消耗试验和强迫游泳试验中的快感缺乏样和抑郁样行为，这些行为被 Bag-1 过度表达所挽救。这些结果表明，Bag-1 介导 GR 运输到线粒体并调节响应 CORT 增加的情感弹性，并提供了对 Bag-1 和 GR 可能有助于精神疾病生理学和发病机制以响应压力荷尔蒙的变化。

更新日期：2020-10-07

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