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Crosstalk between mitochondrial permeability transition and ETC supercomplexes in myocardial infarction

心肌梗死中线粒体通透性转变与 ETC 超复合物之间的串扰

基本信息

批准号：
9769807
负责人：
Sabzali Javadov
金额：
$ 37.5万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-22 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769807
关键词：
ATP Synthesis Pathway Accounting Acute myocardial infarction Animal Model Calcium Cardiac Cardiac Myocytes Cardiolipins Cell Death Cell Survival Cessation of life Clinical Complex Coronary artery Coronary heart disease Development Diffusion Dissociation Electron Transport Electrons Energy Metabolism Extravasation Heart In Vitro Individual Injury Inner mitochondrial membrane Ischemia Knowledge Ligation Mediating Mitochondria Mitochondrial Swelling Modeling Molecular Morbidity - disease rate Mus Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Organelles Outcome Oxidative Phosphorylation Oxidative Stress Oxides Pathogenesis Pathologic Patients Permeability Phospholipids Play Production Rattus Reactive Oxygen Species Reperfusion Injury Reperfusion Therapy Role Therapeutic Intervention Time Treatment Efficacy United States cardioprotection coronary perfusion effective therapy improved in vivo in vivo Model inhibitor/antagonist inorganic phosphate insight knock-down mitochondrial permeability transition pore mortality novel therapeutic intervention oxidation prevent response restoration sanglifehrin A solid state targeted treatment tert-Butylhydroperoxide

项目摘要

ABSRACT Coronary heart disease is the leading cause of morbidity and mortality worldwide. Timely restoration of coronary perfusion known as reperfusion is the only effective therapeutic intervention for protecting the heart from myocardial infarction (MI). Currently, there is no effective therapy for preventing cardiac ischemia-reperfusion (IR) injury. The loss of mitochondrial function plays a crucial role in IR-induced cell death suggesting that protection and restoration of mitochondrial function is pivotal to cell survival in the heart. However, limited knowledge of the mechanisms underlying mitochondria-mediated cell death obscures the development of new mitochondria-targeted cardioprotective compounds. Cardiac IR increases calcium, reactive oxygen species (ROS), and inorganic phosphate levels in mitochondria that induce mitochondrial permeability transition (MPT) concurrently with opening of the non-specific pathological MPT pores in the inner mitochondrial membrane. High mitochondrial ROS (mtROS) also may disintegrate mitochondrial supercomplexes (SCs), predominantly due to oxidation of cardiolipin (CL), a unique mitochondrial phospholipid. SCs are large supramolecular complexes containing individual electron transport chain (ETC) complexes. According to the solid-state model, the assembly of SCs provides high-efficiency electron flux throughout the ETC; it increases ATP synthesis and significantly reduces electron leakage and mtROS production due to short diffusion distances between ETC complexes. The cause-and-effect relationship between MPT induction and SC degradation has not yet been established. We hypothesize that the MPT plays a causal role in the disintegration of mitochondrial SCs, leading to diminished energy metabolism and cell death in cardiac IR. We propose that MPT-induced mitochondrial swelling sensitizes CL to the ROS attack leading to degradation of SCs. The Specific Aims are as follows: (1) Determine the timing of MPT, disintegration of SCs and progression of post-MI injury. We will investigate the association between MPT pore opening and SC degradation, with progression of IR injury, using the animal model of in vivo MI induced by coronary artery ligation with/without subsequent reperfusion. We will also subject WT and tafazzin knockdown (TazKD) mice to cardiac IR to distinguish changes in SC assembling induced by CL oxidation versus CL deficiency. (2) Examine the cause-and-effect relationship between the MPT induction and SC disintegration in response to oxidative stress. We will subject cardiomyocytes/mitochondria with CyP-D (Ppif) and/or tafazzin deficiency to oxidative stress to clarify a cause-and-effect relationship between MPT and SC disintegration. In addition, cardiac mitochondria will be treated with oxidized CL in the presence of MPT inducers/blockers to reveal a causal role of MPT versus CL oxidation in SC degradation. (3) Define if inhibition of MPT, and mtROS scavenging protect synergistically against post-MI injury. These studies will establish whether combined therapy simultaneously targeting mtROS and MPT exerts synergistic cardioprotective effects on cardiac IR. The MPT inhibitor will be administered alone or in combination with mtROS scavengers during in vivo cardiac IR. In addition, WT and TazKD hearts will be subjected to ex vivo IR in the presence of the MPT inhibitor and/or mtROS scavengers. Overall, elucidating the crosstalk mechanisms between MPT and SC degradation will provide new insights into the molecular basis of mitochondria-mediated cell death during cardiac IR. The outcome of this project will allow development of new therapeutic strategies to prevent myocardial IR injury, and improve clinical consequences in patients with acute myocardial infarction through targeting mitochondria.

摘要冠心病是世界范围内发病率和死亡率的主要原因。及时恢复冠脉被称为再灌注的灌注是保护心脏免于再灌注的唯一有效的治疗干预。心肌梗死（MI）。目前，尚无有效的治疗方法来预防心脏缺血-再灌注 (IR)损伤线粒体功能的丧失在IR诱导的细胞死亡中起着至关重要的作用，这表明线粒体功能的保护和恢复对于心脏中的细胞存活至关重要。但受限对大肠杆菌介导的细胞死亡机制的了解掩盖了新的靶向心脏保护化合物。心脏IR增加钙，活性氧 (ROS)和诱导线粒体通透性转换（MPT）的线粒体中的无机磷酸盐水平同时开放线粒体内膜中的非特异性病理性MPT孔。高线粒体ROS（mtROS）也可以分解线粒体超复合物（SC），主要是由于心磷脂（CL），一种独特的线粒体磷脂的氧化。SC是一种大的超分子复合物含有单独的电子传递链（ETC）复合物。根据固态模型，的SC在整个ETC中提供了高效的电子通量;它增加了ATP的合成，由于ETC复合物之间的短扩散距离，减少了电子泄漏和mtROS的产生。的 MPT诱导和SC降解之间的因果关系尚未确定。我们假设MPT在线粒体SC的解体中起着因果作用，导致减少能量代谢和细胞死亡的心脏IR。我们提出，MPT诱导的线粒体肿胀敏化 CL对ROS的攻击导致SC的降解。具体目标如下：（1）确定 MPT的时间、SC的崩解和MI后损伤的进展。我们会调查使用体内的动物模型，冠状动脉结扎伴/不伴后续再灌注诱导MI。我们也会让WT和tafazzin 敲低（TazKD）小鼠心脏IR，以区分CL氧化诱导的SC组装变化与 CL缺乏症。(2)检查MPT诱导和SC崩解之间的因果关系对氧化应激的反应。我们将心肌细胞/线粒体与CyP-D（Ppif）和/或tafazzin 缺乏氧化应激，以澄清MPT和SC崩解之间的因果关系。在此外，将在MPT诱导剂/阻断剂存在下用氧化CL处理心脏线粒体，以揭示 MPT与CL氧化在SC降解中的因果作用。(3)定义是否抑制MPT和mtROS 清除协同保护心肌梗死后损伤。这些研究将确定联合治疗是否同时靶向mtROS和MPT对心脏IR发挥协同的心脏保护作用。在体内心脏IR期间，将单独或与mtROS清除剂组合施用抑制剂。此外，WT和TazKD心脏将在MPT抑制剂和/或mtROS存在下进行离体IR 食腐动物总的来说，阐明MPT和SC退化之间的串扰机制将提供新的深入了解心脏IR期间细胞死亡的分子基础。该项目将允许开发新的治疗策略，以防止心肌IR损伤，并改善临床通过靶向线粒体治疗急性心肌梗死患者。