Bag-1 mediates glucocorticoid receptor trafficking to mitochondria after corticosterone stimulation: Potential role in regulating affective resilience
Bag-1 mediates glucocorticoid receptor trafficking to mitochondria after corticosterone stimulation: Potential role in regulating affective resilience
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Bag-1 在皮质酮刺激后介导糖皮质激素受体转运至线粒体：在调节情感弹性中的潜在作用
DOI：
10.1111/jnc.15211
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发表时间：
2020-10-21
影响因子：
4.7
通讯作者：
Du, Jing
中科院分区：
文献类型：
--
作者：
Luo, Shaolei;Hou, Yangyang;Du, Jing
糖皮质激素受体（GR）应激信号通路内的分子异常涉及线粒体功能障碍，并导致易患与应激相关的精神疾病。 Bcl-2 相关的 athanogene (Bag-1) 是情绪稳定剂的作用靶点。 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 易位至线粒体中的潜在作用。皮质酮 (CORT) 处理 30 分钟和 24 小时后，显着增强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，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，在小鼠的饮用水中给予 CORT 21 天后，线粒体中的 GR 水平显着受损，而 Bag-1 的过度表达则挽救了这种降低。此外，长期暴露于 CORT 会导致蔗糖消耗试验和强迫游泳试验中的快感缺失和抑郁样行为，而这些行为可通过 Bag-1 过度表达而得到挽救。这些结果表明，Bag-1 介导 GR 向线粒体的运输，并调节情感弹性以响应 CORT 的增加，并为 Bag-1 和 GR 响应应激激素的变化而促进精神疾病的生理学和发病机制的机制提供了潜在的见解。
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.