Interaction of mitochondrial fusion and transmembrane potential in diabetic cardiovascular damage

 描述(由申请人提供)：这项建议探索线粒体融合动力学和跨膜电位(∆ψm)的相互作用，作为糖尿病心血管损害的潜在机制和翻译靶点。2型糖尿病是一个迅速增长的公共卫生问题，导致心脏效率下降，成为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，线粒体是负责细胞生物能量学的细胞器网络。然而，至关重要的是，在病理发生之前，在高度氧化的心肌细胞中，线粒体损伤可以持续到什么水平还是个未知数。我们之前对神经肌肉疾病中线粒体结构/功能的研究，利用基于细胞的成像和功能分析，提供了一种现成的方法来解决这一知识缺口。为了维持生物能量平衡，线粒体在一个统一的网状网络(OPA1介导的融合)和单个细胞器的碎片化群体(DRP1介导的分裂)之间平衡它们的组织。跨越线粒体内膜的∆ψm是线粒体融合所必需的，它将细胞器功能和结构动力学联系在一起。值得注意的是，我们的初步数据表明，线粒体融合需要一个明确定义的阈值，即∆ψm的50%。这个阈值与线粒体的分裂活性无关，并且似乎是由Oma1介导的，Oma1是一种应激反应蛋白酶，被证明能在低∆ψm时裂解线粒体OPA1融合蛋白。因此，我们假设这个阈值是由OPA1的表达介导的人线粒体的固有特性，并受到细胞因子的破坏，使心肌细胞发生凋亡。本研究的目的是从机制上探讨这一阈值以及细胞因子介导的损伤对∆ψm和融合动力学的影响，主要是为了寻找一种新的翻译方法来保护心肌线粒体免受细胞因子介导的损伤。这些目标与SC3机制概述的优先事项非常吻合，因为该提案将把线粒体动态平衡的知识扩展到一个主要的公共卫生问题的背景下，并将在一所领先的拉美裔服务机构建立生物医学研究并加强学生研究机会，而该机构并未得到NIH的主要支持。

 DESCRIPTION (provided by applicant): 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 as 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 previous studies of mitochondrial structure/function in neuromuscular disease, utilizing cell-based imaging and functional assays, provide a ready approach to address 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. Strikingly, our preliminary data indicate that a sharply-defined threshold of 50% of ∆ψm is required for mitochondrial fusion. This threshold is independent of mitochondrial fission activity, and appears to be mediated by OMA1, a stress-response protease that has been shown to cleave the mitochondrial OPA1 fusion protein in response to low ∆ψm. Accordingly, we hypothesize that this threshold is an intrinsic property of human mitochondria mediated by expression of OPA1, and is damaged by cytokines, committing cardiac cells to apoptosis. The proposed aims mechanistically explore this threshold and the impacts of cytokine-mediated damage on ∆ψm and fusion dynamics, with major potential for a novel translational approach protecting cardiac mitochondria against cytokine-mediated damage. These aims an excellent fit with the outlined priorites for the SCORE SC3 mechanism, as the proposal will extend knowledge of mitochondrial homeostasis into the context of a leading public health problem, and will build biomedical research and enhance student research access at a leading Hispanic-serving institution that has not been a major recipient of NIH support.