Mitochondrial function and glycolytic switch in pathological cardiac hypertrophy

病理性心脏肥大中的线粒体功能和糖酵解转换

基本信息

批准号：
9925814
负责人：
Rong Tian
金额：
$ 58.64万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925814
关键词：
ATP phosphohydrolase Adenoviruses Binding Cardiac Cardiac Myocytes Cell Culture System Cells Coupled Data Down-Regulation Echocardiography Energy Metabolism Equilibrium Genetic Transcription Glucose Glycolysis HIF1A gene Heart Heart Hypertrophy Heart failure Human Hypertrophy Impairment Ischemia Mediator of activation protein Membrane Potentials Metabolic Metabolism Mitochondria Mitochondrial Proteins Molecular Multinuclear NMR Mus Myocardial NMR Spectroscopy Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Pathologic Phenotype Phenylephrine Physiological Production Proteins Proton-Translocating ATPases Protons Reactive Oxygen Species Reporter Research Rodent Role Signal Transduction Stress Technology Testing Time Up-Regulation Warburg Effect Yeasts base cardiogenesis constriction fatty acid oxidation heart metabolism improved in vivo in vivo Model inhibitor/antagonist knock-down mitochondrial dysfunction mitochondrial metabolism oligomycin sensitivity-conferring protein operation overexpression oxidation prevent response tool

项目摘要

Abstract During the development of heart failure cardiac fuel metabolism switches from predominantly fatty acid oxidation (FAO) to increased reliance on glucose, especially glycolysis. This metabolic remodeling is generally recognized and considered ultimately maladaptive for sustaining myocardial energetics and function. The mechanisms responsible for the switch are poorly understood but appear to be coupled with impaired mitochondrial function. Downregulations of multiple transcriptional mechanisms, such as PPARa or PGC-1a, for FAO have been identified in heart failure. Reduced FAO could release the inhibition of glucose use through Randle cycle and thus promote myocardial glucose utilization. However, this hypothesis does not explain why reduced FAO leads to predominantly glycolysis uncoupled with glucose oxidation, a phenomenon similar to Warburg effect. In addition to decreased FAO, multiple aspects of mitochondrial function, in particular, oxidative phosphorylation, oxidative stress, and redox balance, are also altered in hearts with pathological hypertrophy. These observations raise an intriguing possibility that increased glycolysis is driven by mitochondrial dysfunction although the molecular mediator(s) in the switch are elusive. Recently, we found that the expression of mitochondrial ATPase inhibitor factor 1 (ATPIF1) was increased in rodent hearts or cardiomyocytes (CMs) with pathological hypertrophy. Upregulation of ATPIF1 in non-cardiomyocytes has been shown to increase glycolysis, to trigger mitochondrial hyperpolarization and increase the production of mitochondrial reactive oxygen species (mtROS). In our preliminary study, ATPIF1 overexpression also shifted energy metabolism from mitochondrial oxidation to glycolysis in CMs. Therefore, we asked whether and how ATPIF1 connects mitochondrial function and glycolysis in the heart undergoing pathological hypertrophy. The ATPIF1 is well conserved from yeast to human, and it is known to inhibit the reversed operation of FoF1-ATPase in Complex V (normally functions as ATP synthase) to hydrolyze ATP and thus maintain the proton gradient during reduced membrane potential, such as ischemia. The consequence of ATPIF1 upregulation in the non-ischemic heart is unknown. In the proposed study, we will determine the interaction of ATPIF1 with Complex V under normal and stress conditions and test the hypothesis that increased ATPIF1 inhibits ATP synthase and triggers the metabolic switch to glycolysis via stimulation of HIF1a signaling during pathological hypertrophy. We have generated preliminary data and research tools for the following three specific aims: 1) To test the hypothesis that up-regulation of ATPIF1 increases myocardial glycolysis through enhancing the HIF1α signaling. 2) To determine the molecular interaction of ATPIF1 and FoF1-ATPase and changes of mitochondrial protein interactome under physiological and pathological conditions using quantitative Protein Interaction Reporter (PIR) technology. 3) To determine the in vivo role of ATPIF1 in the metabolic reprogramming and cardiac response to stress.

抽象的在心力衰竭的发展过程中，心脏燃料代谢从主要是脂肪酸氧化转变（粮农组织）增加对葡萄糖的依赖，尤其是糖酵解。这种代谢重塑已得到普遍认可。并被认为最终不适应维持心肌能量和功能。负责这种转换的人们知之甚少，但似乎与线粒体功能受损有关。多种转录机制的下调，例如 PPARa 或 PGC-1a，对于粮农组织来说已经在心力衰竭中发现，减少FAO可以通过兰德尔循环释放对葡萄糖使用的抑制。从而促进心肌葡萄糖的利用。然而，这个假设并不能解释为什么FAO会减少。主要是糖酵解与葡萄糖氧化无关，这种现象类似于瓦伯格效应。除了减少FAO之外，线粒体功能的多个方面，特别是氧化磷酸化，病理性肥大的心脏中氧化应激和氧化还原平衡也会发生改变。提出了一个有趣的可能性，即糖酵解的增加是由线粒体功能障碍驱动的，尽管最近，我们发现线粒体 ATP 酶的表达是难以捉摸的。病理性肥大的啮齿动物心脏或心肌细胞 (CM) 中抑制因子 1 (ATPIF1) 增加。非心肌细胞中 ATPIF1 的上调已被证明可以增加糖酵解，从而触发线粒体超极化并增加线粒体活性氧 (mtROS) 的产生。初步研究，ATPIF1过表达也将能量代谢从线粒体氧化转变为因此，我们询问 ATPIF1 是否以及如何连接线粒体功能和糖酵解。在经历病理性肥大的心脏中。ATPIF1 从酵母到人类都得到了很好的保存，并且它是已知可抑制复合物 V（通常作为 ATP 合酶）中 FoF1-ATPase 的反向操作水解 ATP，从而在膜电位降低（例如缺血）期间保持质子梯度。 ATPIF1 在非缺血性心脏中上调的后果尚不清楚，在拟议的研究中，我们将进行研究。确定正常和应激条件下 ATPIF1 与复合物 V 的相互作用并检验假设增加的 ATPIF1 抑制 ATP 合酶并通过以下途径触发代谢转变为糖酵解在病理性肥大期间刺激 HIF1aα 信号传导我们已经生成了初步数据并进行了研究。研究工具用于以下三个具体目标：1) 检验 ATPIF1 上调的假设通过增强 HIF1α 信号传导增加心肌糖酵解 2) 确定分子。 ATPIF1和FoF1-ATPase相互作用及线粒体蛋白相互作用组的变化使用定量蛋白质相互作用报告仪 (PIR) 检测生理和病理条件 3) 确定 ATPIF1 在代谢重编程和心脏中的体内作用。对压力的反应。