Mitochondrial respirasomes in acute coronary syndromes

 描述（由申请人提供）：缺血性心脏病仍然是工业化国家发病率和死亡率的主要原因，急性冠状动脉综合征后的预后与心肌损伤的程度成正比。越来越多的文献 表明心肌线粒体是组织活力的关键决定因素。最近的临床试验报告说，靶向线粒体显示出减少损伤和改善患者预后的希望。尽管有这些令人兴奋的发现，但在心肌梗死过程中导致线粒体功能障碍的机制尚未完全了解。特别是，我们对线粒体膜的变化如何直接阻碍缺血后线粒体呼吸的理解存在根本性的差距。长期目标是开发新的心脏特异性干预措施，在代谢应激期间保护心脏组织。该提案的目的是阐明线粒体膜脂质环境对缺血后呼吸活性的作用，并确定是否有一种针对线粒体的肽通过优化脂质依赖性呼吸来挽救组织。中心假设是缺血后线粒体呼吸功能由于线粒体内膜分子组织的破坏而受损。这一假设是基于强有力的初步数据，显示缺血-再灌注降低线粒体膜流动性，这阻止了呼吸超复合物的正确组装。此外，初步证据表明，细胞可渗透的心磷脂靶向肽通过挽救膜流动性的破坏来保护心脏。为了实现这些目标，将检验两个具体假设。具体目标1将检验线粒体膜流动性降低促进线粒体功能障碍和再灌注损伤的假设。创新的方法包括评估线粒体膜流动性，使用头基和酰基侧链敏感的探针，同时测量线粒体膜流动性和呼吸，复杂的成像心磷脂动力学在心室肌细胞和完整的心脏，和模型膜系统，重演缺血再灌注期间心脏线粒体的变化。具体目标2将检验呼吸超复合物的功能障碍组装有助于再灌注损伤的假设。缺血后呼吸的综合检查包括呼吸和灌注心脏、透性纤维、分离线粒体和分离呼吸超复合带的复杂成像研究。心磷脂靶向肽在保护线粒体呼吸中的功效将在模型中垂直测试。这项研究具有重要意义，因为它有望扩大对急性冠状动脉综合征期间线粒体脂质和功能性磷脂酶体相互作用的理解。最终，这些研究有可能促进新疗法的开发，减少缺血性心脏病的负担。

 DESCRIPTION (provided by applicant): Ischemic heart disease remains a leading cause of morbidity and mortality in the industrialized world, and prognosis after acute coronary syndromes is directly proportional to the extent of myocardial injury. A growing body of literature suggests that cardiac mitochondria are critical determinants of tissue viability. Recent clinical trials report that targeting mitochondria showed promise in reducing injury and improving patient outcomes. In spite of these exciting findings, the mechanisms that lead to mitochondrial dysfunction during the course of a myocardial infarction are not fully understood. In particular, there is a fundamental gap in our understanding of how changes in mitochondrial membranes directly hinder post-ischemic mitochondrial respiration. The long-term goal is to develop novel mitochondria-specific interventions that preserve cardiac tissue during times of metabolic stress. The objectives of this proposal are to elucidate the role of the mitochondrial membrane lipid environment on post-ischemic respiratory activity, and to determine if a mitochondria-directed peptide salvages tissue by optimizing lipid-dependent respiration. The central hypothesis is that post-ischemic mitochondrial respiratory function is compromised due to a disruption in the molecular organization of the inner mitochondrial membrane. This hypothesis is based on strong preliminary data showing ischemia-reperfusion decreases mitochondrial membrane fluidity, which prevents proper assembly of respiratory super complexes. Furthermore, preliminary evidence indicates that a cell- permeable, cardiolipin-targeted peptide protects the heart by rescuing the disruption in membrane fluidity. To accomplish the objectives, two specific hypotheses will be tested. Specific Aim 1 will test the hypothesis that decreases in mitochondrial membrane fluidity promote mitochondrial dysfunction and reperfusion injury. Innovative approaches include assessment of mitochondrial membrane fluidity using both head group- and acyl side chain-sensitive probes, simultaneous measurement of mitochondrial membrane fluidity and respiration, sophisticated imaging of cardiolipin dynamics in ventricular myocytes and intact hearts, and model membrane systems that recapitulate changes in heart mitochondria during ischemia-reperfusion. Specific Aim 2 will test the hypothesis that dysfunctional assembly of respiratory super complexes contributes to reperfusion injury. A comprehensive examination of post-ischemic respiration includes respiration and sophisticated imaging studies in perfused hearts, permeabilized fibers, isolated mitochondria, and isolated respiratory super complex bands. The efficacy of cardiolipin-targeting peptide in preserving mitochondrial respiration will be tested vertically across models. The proposed research is significant as it is expected to expand understanding of the interaction of mitochondrial lipids and functional respirasomes during acute coronary syndromes. Ultimately, these studies have the potential to foster development of new therapies that reduce the burden of ischemic heart disease.