Interaction of mitochondrial fusion and transmembrane potential in diabetic cardiovascular damage

项目总结/摘要 该建议探讨了线粒体融合动力学和跨膜电位的相互作用 （β-内酰胺酶）作为糖尿病心血管损伤的潜在机制和翻译靶点。2型 糖尿病是一个快速增长的公共卫生问题，导致心脏效率下降 这是导致2型糖尿病患者死亡的主要原因。一系列临床和实验 数据表明，导致糖尿病病理学直接损害的精氨酸介导的炎症， 线粒体，负责细胞生物能量学的细胞器网络。然而，关键是， 目前尚不清楚在高氧化心肌细胞中， 病理学检查我们目前的SC 3支持提供了新的机制见解， 提出的目标：1）探索OMA 1应激反应蛋白酶如何被蛋白酶的损失激活，2） OPA 1水平在决定线粒体融合稳态中的作用，以及3）时间依赖性 对线粒体敏感的线粒体融合动力学的性质。这些实验将利用我们发表的 基于细胞的成像和功能测定，以进一步探索这一知识差距。保持 生物能量稳态，线粒体平衡它们的组织之间的联合，网状网络 （OPA 1介导的融合）和单个细胞器的片段化群体（DRP 1介导的分裂）。 跨线粒体内膜的线粒体膜是线粒体融合所必需的， 细胞器功能和结构动力学：我们以前证明了一个sharp定义的 线粒体融合所需的阈值为34%丝氨酸。引人注目的是，我们目前的数据表明， 类似的阈值存在于心脏来源的细胞中，并且该阈值由OMA 1介导，OMA 1是一种应激因子， 应答蛋白酶，其响应于低细胞凋亡而切割线粒体OPA 1融合蛋白。此外，本发明还 我们的数据表明，OMA 1需要新的分子内结构域来检测线粒体的缺失。我们 该项目将机械地探索这一阈值，以及尼古丁介导的损害的影响 对线粒体压力敏感动力学的时间整合性质。 这项研究有很大的潜力，为保护心脏的新的翻译方法提供信息。 线粒体对抗精氨酸介导的损伤。

PROJECT SUMMARY/ABSTRACT This proposal explores the interaction of mitochondrial fusion dynamics and transmembrane potential (∆ψm) as an underlying mechanism and translational target in diabetic cardiovascular damage. Type 2 diabetes mellitus is a rapidly-increasing public health concern, causing decreased cardiac efficiency which is the leading cause of mortality among Type 2 diabetics. A range of clinical and experimental data suggests that the cytokine-mediated inflammation that drives diabetic pathology directly damages mitochondria, the organellar network responsible for cellular bioenergetics. Crucially, however, it is unknown what level of mitochondrial damage can be sustained in highly-oxidative cardiac cells before pathology ensues. Our current SC3 support has provided novel mechanistic insights motivating the proposed aims: 1) to explore how the OMA1 stress-responsive protease is activated by loss of ∆ψm, 2) the role of OPA1 levels in determining mitochondrial fusion homeostasis, and 3) the time-dependent nature of ∆ψm-sensitive mitochondrial fusion dynamics. These experiments will leverage our published cell-based imaging and functional assays to further explore this gap in knowledge. To maintain bioenergetic homeostasis, mitochondria balance their organization between a united, reticular network (OPA1-mediated fusion) and a fragmented population of individual organelles (DRP1-mediated fission). The ∆ψm across the mitochondrial inner membrane is required for mitochondrial fusion, linking organellar function and structural dynamics: we demonstrated previously that a sharply-defined threshold of 34% ∆ψm is required for mitochondrial fusion. Strikingly, our current data indicates that a similar threshold exists in cardiac-derived cells, and that this threshold is mediated by OMA1, a stress- response protease that cleaves the mitochondrial OPA1 fusion protein in response to low ∆ψm. Further, our data suggests that novel intramolecular domains are required for OMA1 to sense loss of ∆ψm. Our project will mechanistically explore this threshold, as well as the impacts of cytokine-mediated damage on ∆ψm and fusion dynamics and the time-integrated nature of mitochondrial stress-sensitive dynamics. This research has strong potential to inform a novel translational approach to protect cardiac mitochondria against cytokine-mediated damage.