Interaction of mitochondrial fusion and transmembrane potential in diabetic cardiovascular damage

项目摘要/摘要 该方案探讨了线粒体融合动力学和跨膜电位之间的相互作用。 (∆ψm)作为糖尿病心血管损害的潜在机制和翻译靶点。类型2 糖尿病是一个迅速增长的公共健康问题，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，推动糖尿病病理的细胞因子介导的炎症直接损害 线粒体，负责细胞生物能量学的细胞器网络。然而，至关重要的是，它是 在此之前，尚不清楚高氧化心肌细胞的线粒体损伤程度 病理学随之而来。我们目前的SC3支持提供了新的机械洞察力，以激励 提出的目标：1)探索∆ψm的缺失是如何激活Oma1应激反应酶的，2) OPA1水平在决定线粒体融合动态平衡中的作用，以及3)时间依赖性 ∆ψm敏感线粒体融合动力学的本质。这些实验将利用我们发表的 基于细胞的成像和功能分析，以进一步探索这一知识差距。维护 生物能量动态平衡，线粒体在一个统一的网状网络之间平衡它们的组织 (OPA1介导的融合)和单个细胞器的碎片化群体(Drp1介导的分裂)。 跨越线粒体内膜的∆ψm是线粒体融合、连接所必需的。 细胞器功能和结构动力学：我们之前证明了一个明确定义的 线粒体融合所需阈值为34%∆ψm。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，并且这个阈值是由OMA1介导的，OMA1是一种应激- 响应酶，切割线粒体OPA1融合蛋白以响应低∆ψm。此外， 我们的数据表明，OMA1需要新的分子内结构域来感知∆ψm的丢失。 项目将机械地探索这一门槛，以及细胞因子介导的损害的影响 关于∆ψm和融合动力学以及线粒体应力敏感动力学的时间整合性质。 这项研究有很大的潜力提供一种新的翻译方法来保护心脏 线粒体对抗细胞因子介导的损伤。

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.