PDF(Pubmed)
Abstract：
Rationale: Recent evidence highlights the pivotal role of mitochondrial dysfunction in mood disorders, but the mechanism involved remains unclear. We studied whether the Hippo/YAP/14-3-3η signaling pathway mediates mitochondrial abnormalities that result in the onset of major depressive disorder (MDD) in a mouse model. Methods: The ROC algorithm was used to identify a subpopulation of mice that were exposed to chronic unpredictable mild stress (CUMS) and exhibited the most prominent depressive phenotype (Dep). Electron microscopy, biochemical assays, quantitative PCR, and immunoblotting were used to evaluate synaptic and mitochondrial changes in the basolateral amygdala (BLA). RNA sequencing was used to explore changes in the Hippo pathway and downstream target genes. In vitro pharmacological inhibition and immunoprecipitation was used to confirm YAP/14-3-3η interaction and its role in neuronal mitochondrial dysfunction. We used virus-mediated gene overexpression and knockout in YAP transgenic mice to verify the regulatory effect of the Hippo/YAP/14-3-3η pathway on depressive-like behavior. Results: Transcriptomic data identified a large number of genes and signaling pathways that were specifically altered from the BLA of Dep mice. Dep mice showed notable synaptic impairment in BLA neurons, as well as mitochondrial damage characterized by abnormal mitochondrial morphology, compromised function, impaired biogenesis, and alterations in mitochondrial marker proteins. The Hippo signaling pathway was activated in Dep mice during CUMS, and the transcriptional regulatory activity of YAP was suppressed by phosphorylation of its Ser127 site. 14-3-3η was identified as an important co-regulatory factor of the Hippo/YAP pathway, as it can respond to chronic stress and regulate cytoplasmic retention of YAP. Importantly, the integrated Hippo/YAP/14-3-3η pathway mediated neuronal mitochondrial dysfunction and depressive behavior in Dep mice. Conclusion: The integrated Hippo/YAP/14-3-3η pathway in the BLA neuron is critical in mediating depressive-like behaviors in mice, suggesting a causal role for this pathway in susceptibility to chronic stress-induced depression. This pathway therefore may present a therapeutic target against mitochondrial dysfunction and synaptic impairment in MDD.
摘要：
基本原理：最近的证据强调了线粒体功能障碍在情绪障碍中的关键作用，但其机制尚不清楚.我们研究了Hippo/YAP/14-3-3η信号通路是否介导线粒体异常，从而导致小鼠模型中重度抑郁症（MDD）的发作。方法：ROC算法用于鉴定暴露于慢性不可预测的轻度应激（CUMS）并表现出最突出的抑郁表型（Dep）的小鼠亚群。电子显微镜,生化化验,定量PCR,免疫印迹用于评估基底外侧杏仁核（BLA）的突触和线粒体变化。RNA测序用于探索Hippo途径和下游靶基因的变化。使用体外药理学抑制和免疫沉淀来确认YAP/14-3-3η相互作用及其在神经元线粒体功能障碍中的作用。我们在YAP转基因小鼠中使用病毒介导的基因过表达和敲除来验证Hippo/YAP/14-3-3η途径对抑郁样行为的调节作用。结果：转录组数据鉴定了大量基因和信号通路，这些基因和信号通路从Dep小鼠的BLA中特异性改变。Dep小鼠在BLA神经元中表现出明显的突触损伤，以及以线粒体形态异常为特征的线粒体损伤，功能受损，受损的生物发生，和线粒体标记蛋白的改变。在CUMS期间，Dep小鼠的Hippo信号通路被激活，YAP的转录调节活性被其Ser127位点的磷酸化抑制。14-3-3η被确定为Hippo/YAP途径的重要共调节因子，因为它可以响应慢性应激并调节YAP的细胞质保留。重要的是,整合的Hippo/YAP/14-3-3η途径介导了Dep小鼠的神经元线粒体功能障碍和抑郁行为。结论：BLA神经元中整合的Hippo/YAP/14-3-3η通路在介导小鼠抑郁样行为中起着至关重要的作用。提示该途径在慢性应激诱导的抑郁症易感性中的因果作用。因此，该途径可能是针对MDD中线粒体功能障碍和突触损伤的治疗靶标。
