Interaction of mitochondrial fusion and transmembrane potential in diabetic cardiovascular damage

 描述（由申请人提供）：本提案探讨了线粒体融合动力学和跨膜电位（跨膜电位）的相互作用，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，导致心脏效率降低，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，驱动糖尿病病理学的精氨酸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，在病理学恶化之前，在高度氧化的心脏细胞中可以维持何种水平的线粒体损伤是未知的。我们以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测定，提供了一种现成的方法来解决这一知识缺口。为了维持生物能量稳态，线粒体在联合的网状网络（OPA 1介导的融合）和单个细胞器的碎片化群体（DRP 1介导的裂变）之间平衡其组织。跨线粒体内膜的线粒体膜是线粒体融合所必需的，连接细胞器功能和结构动力学。引人注目的是，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50%的线粒体膜。该阈值独立于线粒体分裂活性，并且似乎是由OMA 1介导的，OMA 1是一种应激反应蛋白酶，已显示其响应于低的线粒体蛋白酶而切割线粒体OPA 1融合蛋白。因此，我们假设该阈值是由OPA 1表达介导的人线粒体的固有特性，并且被细胞因子破坏，从而使心脏细胞凋亡。所提出的目标从机制上探讨了这一阈值以及精氨酸介导的损伤对线粒体和融合动力学的影响，这是一种保护心脏线粒体免受精氨酸介导的损伤的新型翻译方法的主要潜力。这些目标与SCORE SC 3机制的优先事项非常吻合，因为该提案将把线粒体稳态的知识扩展到一个主要的公共卫生问题的背景下，并将建立生物医学研究，并加强学生在一个领先的西班牙裔服务机构的研究机会，该机构不是NIH支持的主要接受者。

 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.