Targeting neuronal Drp1-Fis1 interactions to mediate glucocorticoid-induced pathologies

近80%的成年人报告称，他们在日常生活中感到压力很大。就像长期的压力暴露 与负面的健康后果相关，了解这种压力暴露的影响对于 防止下游病变的发展。线粒体是动态细胞器，具有 在许多对细胞生存至关重要的功能中发挥作用。一个这样的功能包括合成和 应激时糖皮质激素的释放。有趣的是，糖皮质激素也会影响 线粒体功能，高水平会导致功能障碍和线粒体碎裂。线粒体 研究表明，碎裂可以激活炎性小体，增加促炎水平。 细胞因子，这与压力相关的负面行为结果有关。线粒体 片段化部分依赖于一种称为动力蛋白相关蛋白1(Drp1)的裂变因子及其相互作用 其受体位于线粒体外膜上。虽然研究表明，慢性压力 诱导片段化，DRp1及其受体之间的精确相互作用，以及慢性不可预测 压力仍不清楚。我们的研究将测试长期不可预测的压力是否会导致过度 糖皮质激素升高导致线粒体碎裂，增加DRp1的募集到 线粒体外膜以受体专一性的方式。然后我们将研究是否中断了 这些特定的Drp1-受体相互作用可以防止线粒体断裂和随后的 炎症和下游行为改变。

Nearly 80% of adults report feeling high levels of stress in their daily lives. As chronic stress exposure is associated with negative health outcomes, understanding the effects of this stress exposure is crucial to preventing the development of downstream pathologies. Mitochondria are dynamic organelles that have roles in a number of functions that are crucial for cell survival. One such function includes the synthesis and release of glucocorticoids in response to stress exposure. Interestingly, glucocorticoids can also impact mitochondrial function, with high levels inducing dysfunction and mitochondrial fragmentation. Mitochondrial fragmentation has been shown to activate inflammasomes and increase levels of proinflammatory cytokines, which have been linked to negative behavioral outcomes linked to stress. Mitochondrial fragmentation relies in part on a fission factor called Dynamin-related protein 1 (Drp1) and its interactions with its receptors on the mitochondrial outer membrane. While studies have shown that chronic stress induces fragmentation, the precise interactions between Drp1, its receptors, and chronic unpredictable stress remains unclear. Our studies will test whether chronic unpredictable stress induces excessive mitochondrial fragmentation via the elevation of glucocorticoids that increase Drp1 recruitment to the mitochondrial outer membrane in a receptor-specific manner. We will then examine whether disruption of these specific Drp1-receptor interactions can prevent mitochondrial fragmentation and subsequent inflammation and downstream behavioral alterations.