Mitochondrial Dysfunction in heart Failure

心力衰竭中的线粒体功能障碍

基本信息

批准号：
7750206
负责人：
Charles Leslie Hoppel
金额：
$ 28.67万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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：
2009-08-14 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7750206
关键词：
Acute Address Adrenergic Agents Affect Agonist Bioenergetics Canis familiaris Cardiac Cardiolipins Chronic Citric Acid Cycle Collaborations Complex Coronary Cultured Cells Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Analyses Defect Diet Dopamine Electron Transport Electrons Energy Metabolism Evaluation Extravasation Failure Functional disorder Generations Genes Glutamates Goals Heart Heart Mitochondria Heart Rate Heart failure Histology Human Resources Hypertrophy Individual Inner mitochondrial membrane Instruction International Investigation Knockout Mice Left Ventricular Function Manuscripts Metabolic Metabolism Mitochondria Mitochondrial Matrix Mixed Function Oxygenases Modeling Modification Mus Myocardial Nerve Norepinephrine Outer Mitochondrial Membrane Oxidases Oxidative Phosphorylation Pathway interactions Performance Phenotype Phosphorylation Phosphorylation Site Phosphotransferases Portraits Preparation Principal Investigator Production Protein Isoforms Proteins Proteomics Quality Control Reactive Oxygen Species Research Design Role Sampling Serine Serine/Threonine Phosphorylation Severities Signal Transduction Site Site-Directed Mutagenesis Superoxides Therapeutic Threonine Time Transgenic Mice Translations Travel Voltage-Dependent Anion Channel Work adrenergic complex IV constriction cytochrome c oxidase design feeding gel electrophoresis improved inhibitor/antagonist mRNA Expression meetings mitochondrial dysfunction mitochondrial membrane nepicastat novel oxidation prevent research study respiratory

项目摘要

The central goal of this project is to define the mechanism of myocardial bioenergetic failure in heart failure (HF) and design therapeutic strategies targeted to improve mitochondrial energy production. We recently found a dramatic decrease in oxidative phosphorylation (OXPHOS) of heart mitochondria in canine moderate severity micromebolism-induced HF. The mitochondrial defect does not lie in the total amount and activity of individual electron transport chain complexes but in their assembly in supercomplexes (respirasomes). Complex IV not incorporated in respirasomes contains an increased content of serine and threonine phosphorylation in mitochodria isolated from HF compared with the control. We hypothesize that HF-induced adrenergic stimulation increases C3^osolic cAMP which is transported into the mitochondrial intermembrane space through the mitochondrial outer membrane voltage-dependent anion channel (VDAC) and activates the mitochondrial cAMP dependent kinase (mtPKA). mt PKA-induced phosphorylation of matrix-exposed serine and threonine residues of cytochrome c oxidase (COX) subunits impairs the incorporation of COX into supercomplexes, reduces the amount of fijnctional respirasomes, and decreases OXPHOS of heart mitochondria. Complexes I and III not incorporated in respirasomes facilitate electron leakage and produce superoxide, which causes oxidative modifications of both mitochondrial matrix and myofibrillar proteins, with decreased contractile performance. Experiments will be performed in the well established canine coronary microembolization model ofHF, transgenic mice and cultured cells. Specific aim 1 wil investigate mitochondrial respirasome organization, OXPHOS, ATP production, and ROS generation in moderate severity and severe canine HF. Specific aim 2 will identify the role of the adrenergic stimulation in disruption of the assembly of mitochondrial respirasomes in HF. Specific aim 3 will delineate the mechanistic pathway responsible for the translation of the adrenergic signal into mitochondrial alterations. Specific aim 4 will identify the specific mitochondrial targets for the cAMP-induced phosphorylation and their functional consequences. Specific aim 5 proposes a rational approach for therapeutic strategies that targets cAMP/mtPKA signaling with the attempt to prevent mitochondrial ROS generation, RELEVANCE (See instructions):

该项目的中心目标是确定心力衰竭（HF）中心肌生物能衰竭的机制并设计旨在改善线粒体能量产生的治疗策略。我们最近发现了一个中度严重程度的犬心脏线粒体氧化磷酸化 (OXPHOS) 显着降低微代谢诱发的心力衰竭。线粒体缺陷并不在于个体线粒体的总量和活性电子传递链复合物，但在超级复合物（呼吸体）中组装。复杂 IV 不纳入呼吸体中的丝氨酸和苏氨酸磷酸化含量增加从 HF 中分离出的线粒体与对照相比。我们假设 HF 诱导的肾上腺素能刺激增加 C3^solic cAMP，通过转运到线粒体膜间隙线粒体外膜电压依赖性阴离子通道 (VDAC) 并激活线粒体 cAMP 依赖性激酶 (mtPKA)。 mt PKA 诱导的基质暴露丝氨酸和苏氨酸磷酸化细胞色素 C 氧化酶 (COX) 亚基的残基会损害 COX 掺入超复合物，降低功能性呼吸体的数量，并减少心脏线粒体的 OXPHOS。配合物 I 和 III 不纳入呼吸体促进电子泄漏并产生超氧化物，从而导致氧化线粒体基质和肌原纤维蛋白均发生改变，收缩性能下降。实验将在完善的犬冠状动脉微栓塞模型中进行，转基因小鼠和培养细胞。具体目标 1 将研究线粒体呼吸体组织，中度和重度犬心衰中的 OXPHOS、ATP 生成和 ROS 生成。具体目标2将确定肾上腺素能刺激在心力衰竭中线粒体呼吸体组装破坏中的作用。具体目标 3 将描述负责将肾上腺素能信号转化为线粒体改变。具体目标 4 将确定 cAMP 诱导的特定线粒体靶标磷酸化及其功能后果。具体目标 5 提出了合理的治疗方法以 cAMP/mtPKA 信号传导为目标的策略，试图阻止线粒体 ROS 生成，相关性（参见说明）：