Regulation of Fuel Utilization by Lysine Acetylation in the Failing Heart

赖氨酸乙酰化对衰竭心脏中燃料利用的调节

• 批准号: 9767853
• 负责人: Iain Scott
• 金额: $ 48.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767853
• 关键词: Ablation; Acetyl Coenzyme A; Acetylation; Acetyltransferase; Address; Affect; Area; Biochemical; Bioenergetics; Biology; Cardiac; Cardiac Myocytes; Cardiac Output; Cell Culture Techniques; Cells; Cessation of life; Clinical; Coronary Arteriosclerosis; Data; Defect; Diabetes Mellitus; Diet; Enzymes; Fatty Acids; Future; Genetic; Glucose; Heart; Heart failure; Homeostasis; Human; Hypertrophy; In Vitro; Knockout Mice; Knowledge; Lead; Life Style; Link; Literature; Lysine; Measurement; Mediating; Metabolic; Metabolic Control; Mitochondria; Mitochondrial Proteins; Modeling; Modification; Mus; Myocardial dysfunction; Myocardium; Nutrient Depletion; Obesity; Operative Surgical Procedures; Outcome; Output; Pathway interactions; Positioning Attribute; Post-Translational Protein Processing; Process; Production; Protein Acetylation; Proteomics; Regulation; Risk Factors; Series; Societies; Solid; Starvation; Stress; Surgical Models; System; Techniques; Testing; Therapeutic Intervention; Tissues; United States; cardiogenesis; detection of nutrient; enzyme activity; experimental study; fatty acid oxidation; heart function; improved; in vivo; insight; mitochondrial dysfunction; mitochondrial metabolism; mouse model; new therapeutic target; novel; novel therapeutics; oxidation; preference; pressure; prevent; tool

Abstract Heart failure affects six million people in the United States, and is listed as a causative factor in more than 10% of deaths. The development of heart failure is linked to several risk factors (including coronary artery disease, obesity and diabetes), which are increasingly prevalent in Western societies due to diet and other lifestyle choices. While clinical outcomes have improved over the last three decades, there remain gaps in our knowledge surrounding the cellular mechanisms that regulate cardiac function. One such gap, and the scientific focus of this application, is the regulation of fuel substrate utilization by mitochondria in the heart. Mitochondria provide 95% of the energy required by healthy hearts to maintain contractility, and defects in mitochondrial bioenergetic activity lead to cardiac energy starvation and heart failure. Mitochondria in the heart normally provide this energy through the oxidation of fatty acids; however, during heart failure cardiomyocytes switch to other fuels like glucose. While changes in cardiac substrate preference in heart failure have been well characterized, we do not fully understand the cellular mechanisms that regulate this process. Our data, and the current literature, show that mitochondrial function is regulated by lysine acetylation, a post-translational modification that uses fuel-derived acetyl-CoA as a substrate. We recently identified GCN5L1 as the first component of the mitochondrial acetyltransferase machinery, and showed that GCN5L1-mediated acetylation controls mitochondrial bioenergetics in vitro. The objective of this proposal is to understand how GCN5L1 acetylation impacts mitochondrial bioenergetics in the heart, and to investigate how dysregulated energy substrate utilization can lead to mitochondrial dysfunction, cardiac energy depletion and heart failure. We will achieve this objective by addressing the following questions: (1) How does GCN5L1 control fatty acid oxidation in healthy hearts? (2) How does GCN5L1 control substrate utilization during heart failure progression? (3) How does GCN5L1 regulate cardiac mitochondrial degradation? To answer these questions, we will use a series of in vivo murine heart failure models and in vitro cell culture studies, combined with metabolic, proteomic and biochemical techniques, to examine the biology of GCN5L1. We expect that this series of experiments will provide important new insights on mitochondrial energy substrate regulation, and will highlight GCN5L1 as a crucial component in the control of metabolic fuel choice, bioenergetics and mitochondrial turnover in the heart.

摘要 在美国，心力衰竭影响着600万人，超过10%的人被列为致病因素 死亡的威胁。心力衰竭的发展与几个危险因素有关(包括冠状动脉疾病、 肥胖和糖尿病)，由于饮食和其他生活方式，在西方社会越来越普遍 选择。虽然临床结果在过去30年中有所改善，但在我们的 围绕调节心脏功能的细胞机制的知识。一个这样的差距，和 这一应用的科学焦点是通过心脏中的线粒体调节燃料底物的利用。 线粒体提供了健康心脏维持收缩能力所需能量的95%，而心脏功能缺陷 线粒体的生物能量活动导致心脏能量匮乏和心力衰竭。心脏中的线粒体 正常情况下，这种能量是通过脂肪酸的氧化提供的；然而，在心力衰竭期间，心肌细胞 换成其他燃料，比如葡萄糖。虽然心力衰竭患者心脏底物偏好的变化是好的 我们并不完全了解调控这一过程的细胞机制。我们的数据，以及 目前的文献表明，线粒体的功能受翻译后赖氨酸乙酰化的调节。 使用燃料衍生的乙酰-辅酶A作为底物的修饰。我们最近确定GCN5L1是第一个 线粒体乙酰转移酶机制的组成部分，并表明GCN5L1介导的乙酰化 在体外控制线粒体生物能量学。这项建议的目标是了解GCN5L1如何 乙酰化影响心脏线粒体生物能量学，并调查能量失调 底物利用可导致线粒体功能障碍、心脏能量耗竭和心力衰竭。我们会 通过解决以下问题来实现这一目标：(1)GCN5L1如何控制脂肪酸氧化 在健康心脏中？(2)GCN5L1如何在心力衰竭进展过程中控制底物利用？(3)如何 GCN5L1是否调节心肌线粒体降解？为了回答这些问题，我们将使用一系列 体内小鼠心力衰竭模型和体外细胞培养研究，结合代谢、蛋白质组学和 生化技术，检测GCN5L1的生物学特性。我们预计，这一系列实验将 为线粒体能量底物调控提供了重要的新见解，并将突出GCN5L1作为一种 在控制新陈代谢燃料选择、生物能量学和心脏线粒体周转中起关键作用。