Rescue and Role of Complex I in myocardial ischemic injury

复合物I在心肌缺血损伤中的拯救及作用

基本信息

批准号：
7822200
负责人：
Roberta A. Gottlieb
金额：
$ 2.24万
依托单位：
SAN DIEGO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2010-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7822200
关键词：
Affinity Apoptosis Apoptotic Arachidonic Acids Binding Bypass Cardiolipins Caspase Cell Death Cell Survival Cells Complex Data Dissociation Down-Regulation Family member Fatty Acids Genes Genetic Heart Heart failure Indium Injury Ischemia Knockout Mice Lead Light MAPK14 gene Mediating Mediator of activation protein Membrane Mitochondria Mitochondrial DNA Mitochondrial Proteins Mitochondrial Swelling Modeling Molecular Multienzyme Complexes Mus Muscle Cells Myocardial Myocardial Infarction Myocardial Ischemia NADH oxidoreductase Necrosis Neurons Outcome Oxidative Phosphorylation Pathway interactions Peripheral Phospholipase Process Production Proteins Proton Pump Reperfusion Injury Reperfusion Therapy Role Rupture Simulate Source Superoxides Swelling Testing Thinking Transgenic Mice Yeasts base cyclophilin D cytochrome c functional restoration in vivo mitochondrial membrane mitochondrial permeability transition pore novel overexpression programs public health relevance

项目摘要

DESCRIPTION (provided by applicant): Considerable progress has been made in our understanding of apoptosis mediated by permeabilization of the mitochondrial membrane by pro-apoptotic Bcl-2 family members. However, in the context of myocardial ischemia/reperfusion injury, a significant mechanism of cell death is catastrophic mitochondrial swelling mediated by the mitochondrial permeability transition pore (MPTP). In our studies of HL-1 myocytes subjected to simulated ischemia and reperfusion, Bax and Bid recruitment to mitochondria occurs after and is dependent upon MPTP. We propose to determine whether this is the case in vivo. In ischemia/reperfusion, a mitochondrial phospholipase (iPLA2) is activated and liberates arachidonic acid, which contributes to superoxide production and cell death through activation of the MPTP. We propose to identify the relevant target of arachidonic acid in the mitochondrion. The established view of the MPTP comprising VDAC in the outer membrane, ANT in the inner membrane, and cyclophilin D (matrix/inner membrane) has been questioned in light of recent studies showing that the MPTP can still open in VDAC-null mice, ANT-null mice, and cyclophilin D-null mice, although the threshold is altered. Evidence that has accumulated in parallel to the traditional view of the MPTP has implicated oxidative phosphorylation Complex I as a key element in the MPTP. We now present new evidence derived from cyclophilin D-overexpressing mice that further supports a role for Complex I in the MPTP. We hypothesize that arachidonic acid and cyclophilin D interact with Complex I to regulate pore opening. PUBLIC HEALTH RELEVANCE: Understanding the molecular processes that take place during and after a heart attack may lead to new therapies for ischemic heart disease and heart failure. We will explore the basis for catastrophic mitochondrial swelling in myocardial ischemia and reperfusion. We will identify the fatty acids that contribute to mitochondrial damage, as well as the mitochondrial proteins that are involved. We will develop a novel protein therapy for treatment of heart damage after a heart attack that will bypass the damaged mitochondrial enzyme complex to restore function.

描述（由申请人提供）：我们对促凋亡 Bcl-2 家族成员对线粒体膜的透化介导的细胞凋亡的理解已经取得了相当大的进展。然而，在心肌缺血/再灌注损伤的情况下，细胞死亡的一个重要机制是由线粒体通透性转换孔（MPTP）介导的灾难性线粒体肿胀。在我们对 HL-1 肌细胞进行模拟缺血和再灌注的研究中，Bax 和 Bid 募集到线粒体发生在 MPTP 之后，并且依赖于 MPTP。我们建议确定体内情况是否如此。在缺血/再灌注中，线粒体磷脂酶 (iPLA2) 被激活并释放花生四烯酸，花生四烯酸通过激活 MPTP 促进超氧化物的产生和细胞死亡。我们建议确定线粒体中花生四烯酸的相关靶标。 MPTP 包含外膜中的 VDAC、内膜中的 ANT 和亲环蛋白 D（基质/内膜）的既定观点受到质疑，因为最近的研究表明 MPTP 仍然可以在 VDAC 无效的小鼠中打开，ANT -null 小鼠和亲环蛋白 D-null 小鼠，尽管阈值发生了改变。与 MPTP 的传统观点同时积累的证据表明，氧化磷酸化复合物 I 是 MPTP 中的关键元素。我们现在提出来自亲环蛋白 D 过度表达小鼠的新证据，进一步支持复合物 I 在 MPTP 中的作用。我们假设花生四烯酸和亲环蛋白 D 与复合物 I 相互作用来调节孔隙开放。公共卫生相关性：了解心脏病发作期间和之后发生的分子过程可能会导致缺血性心脏病和心力衰竭的新疗法。我们将探讨心肌缺血和再灌注时灾难性线粒体肿胀的基础。我们将确定导致线粒体损伤的脂肪酸以及相关的线粒体蛋白质。我们将开发一种新型蛋白质疗法，用于治疗心脏病发作后的心脏损伤，该疗法将绕过受损的线粒体酶复合物以恢复功能。