Mitochondrial respirasomes in acute coronary syndromes

描述(申请人提供)：在工业化世界中，缺血性心脏病仍然是发病率和死亡率的主要原因，急性冠脉综合征的预后与心肌损伤的程度成正比。越来越多的文学作品 提示心肌线粒体是组织存活的关键决定因素。最近的临床试验报告，靶向线粒体在减少损伤和改善患者预后方面显示出希望。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不完全清楚。特别是，在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上存在着根本的差距。长期目标是开发新的线粒体特异性干预措施，在代谢应激期间保护心脏组织。该方案的目的是阐明线粒体膜脂环境对缺血后呼吸活动的作用，并确定线粒体导向的多肽是否通过优化脂质依赖的呼吸来挽救组织。中心假说是，由于线粒体内膜分子组织的破坏，缺血后线粒体的呼吸功能受到损害。这一假说是建立在强大的初步数据基础上的，这些数据表明，缺血再灌注会降低线粒体膜流动性，从而阻止呼吸超复合体的正确组装。此外，初步证据表明，一种细胞通透性的、心磷脂靶向性的多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，将测试两个具体目标。特定目的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说。创新方法包括使用头基和酰基侧链敏感探针评估线粒体膜流动性，复杂的心肌细胞和完整心脏心磷脂动态成像，以及概括缺血-再灌注期间心脏线粒体变化的模型膜系统。特定目标2将检验呼吸超复合体功能障碍组装导致再灌注损伤的假说。对缺血后呼吸的全面检查包括对灌流的心脏、通透性纤维、分离的线粒体和分离的呼吸超复合体条带的呼吸研究。心磷脂靶向多肽在保存线粒体呼吸方面的有效性将在模型中进行垂直测试。这项拟议的研究具有重要意义，因为它有望扩大对急性冠脉综合征期间线粒体脂质和功能性呼吸系统疾病相互作用的理解。最终，这些研究有可能促进新疗法的开发，以减轻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 mitochondria-directed peptides salvage 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 supercomplexes. 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 aims 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 headgroup- and acyl side chain-sensitive probes, 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 supercomplexes contributes to reperfusion injury. A comprehensive examination of post-ischemic respiration includes respiration studies in perfused hearts, permeabilized fibers, isolated mitochondria, and isolated respiratory supercomplex 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.