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):

该项目的核心目标是定义心力衰竭中心肌生物能力衰竭的机制（HF）和设计旨在改善线粒体能量生产的治疗策略。我们最近发现了犬中等严重程度中心脏线粒体的氧化磷酸化（OXPHOS）急剧减少微观骨质引起的HF。线粒体缺陷不在于个体的总量和活动电子传输链复合物，但在超级复合物（呼吸症）中的组装中。复合体IV不掺入呼吸道中包含丝氨酸和苏氨酸磷酸化的含量增加与对照相比，从HF中分离出的线粒体。我们假设HF诱导的肾上腺素能刺激增加了C3^的c3^可容纳营，该营地通过线粒体外膜电压依赖性阴离子通道（VDAC）并激活线粒体营地依赖激酶（MTPKA）。 MT PKA诱导的基质丝氨酸和苏氨酸的磷酸化细胞色素C氧化酶（COX）亚基的残基会损害Cox掺入超复合物中，减少 fijnctiation呼吸道的量，并降低了心脏线粒体的OXPHOS。复合体I和III不是掺入呼吸道体有助于电子泄漏并产生超氧化物，从而引起氧化性氧化线粒体基质和肌原纤维蛋白的修饰，收缩性能降低。实验将在良好的犬冠状动脉微栓塞模型中进行，转基因小鼠和培养细胞。特定目的1 WIL调查线粒体呼吸症组织，中等严重性和严重的犬HF中的Oxphos，ATP产生和ROS产生。具体目标2将确定肾上腺素能刺激在HF中线粒体呼吸道组装中断中的作用。具体目标3将描述负责肾上腺素信号转化为的机械途径线粒体改变。特定的目标4将确定营地引起的特定线粒体目标磷酸化及其功能后果。特定目标5提出了一种理性治疗方法针对营地/mtpka信号的策略，试图防止线粒体ROS产生，相关性（请参阅说明）：