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: 9324419
• 负责人: Iain Scott
• 金额: $ 46.94万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324419
• 关键词: Acetyl Coenzyme A; Acetylation; Acetyltransferase; Address; Affect; Area; Biochemical; Bioenergetics; Biology; Carbohydrates; Cardiac; Cardiac Myocytes; Cell Culture Techniques; Cells; Cessation of life; Clinical; Coronary Arteriosclerosis; Coupling; Data; Defect; Development; Diabetes Mellitus; Diet; Enzymes; Fatty Acids; Fatty acid glycerol esters; Future; Genetic; Glucose; Heart; Heart failure; Human; In Vitro; Knockout Mice; Knowledge; Lead; Life Style; Link; Literature; Lysine; Mediating; Medical; Metabolic Control; Mitochondria; Mitochondrial Proteins; Modeling; Modification; Mus; Myocardial dysfunction; Myocardium; Obesity; Operative Surgical Procedures; Outcome; Output; Pathway interactions; Positioning Attribute; Post-Translational Protein Processing; Process; Proteomics; Regulation; Risk Factors; Series; Societies; Solid; Staging; Starvation; System; Techniques; Testing; Therapeutic Intervention; United States; abstracting; base; detection of nutrient; enzyme activity; fatty acid oxidation; improved; improved outcome; in vitro Model; in vivo; insight; meetings; metabolomics; mitochondrial dysfunction; mouse model; new therapeutic target; novel; novel therapeutics; oxidation; preference; prevent; research study; 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 they 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 normal and failing hearts? (2) What acetyl modifications regulate mitochondrial fuel utilization enzymes during early- and late-stage heart failure? (3) How does GCN5L1 regulate cardiac mitochondrial turnover under normal and energy-depleted states? To answer these questions, we will use a series of in vivo murine heart failure models and in vitro cell culture studies, combined with metabolomic, 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.

抽象的 心力衰竭影响美国 600 万人，并被列为 10% 以上的致病因素 死亡人数。心力衰竭的发生与多种危险因素有关（包括冠状动脉疾病、 由于饮食和其他生活方式的原因，肥胖和糖尿病在西方社会越来越普遍 选择。尽管过去三十年临床结果有所改善，但我们的研究仍存在差距 围绕调节心脏功能的细胞机制的知识。一个这样的差距，以及 该应用的科学焦点是心脏中线粒体对燃料底物利用的调节。 线粒体提供健康心脏维持收缩力所需能量的 95%，而线粒体缺陷 线粒体生物能活动导致心脏能量匮乏和心力衰竭。线粒体在心脏 通常通过脂肪酸的氧化提供这种能量；然而，在心力衰竭期间，他们会转而使用 其他燃料，如葡萄糖。虽然心力衰竭中心脏底物偏好的变化已得到很好的证实 但我们并不完全了解调节这一过程的细胞机制。我们的数据，以及 目前的文献表明，线粒体功能受到赖氨酸乙酰化的调节，赖氨酸乙酰化是一种翻译后蛋白 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 体外控制线粒体生物能。该提案的目的是了解 GCN5L1 如何 乙酰化影响心脏中的线粒体生物能，并研究能量失调如何 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。我们将 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 在正常和失败的心中？ (2)哪些乙酰基修饰调节线粒体燃料利用酶 早期和晚期心力衰竭期间？ (3)GCN5L1如何调节心肌线粒体周转 正常状态和能量耗尽状态？为了回答这些问题，我们将使用一系列体内小鼠心脏 失效模型和体外细胞培养研究，结合代谢组学、蛋白质组学和生物化学 技术来检查 GCN5L1 的生物学。我们期望这一系列的实验能够提供 关于线粒体能量底物调节的重要新见解，并将强调 GCN5L1 作为一个关键的 控制心脏代谢燃料选择、生物能量学和线粒体周转的成分。