Regulation of Fuel Utilization by Lysine Acetylation in the Failing Heart

摘要 心力衰竭影响着美国600万人，并且被列为超过10%的致病因素。 死亡心力衰竭的发生与几个风险因素有关（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，这些疾病在西方社会越来越普遍 选择.虽然临床结果在过去三十年中有所改善，但我们的研究仍存在差距。 了解调节心脏功能的细胞机制。一个这样的差距， 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。 线粒体提供了健康心脏维持收缩力所需能量的95%，而线粒体缺陷则导致心脏收缩力下降。 线粒体生物能量活动导致心脏能量饥饿和心力衰竭。心脏中的线粒体 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，心肌细胞 改用葡萄糖等其他燃料。虽然心力衰竭中心脏底物偏好的变化已经很好地 由于这些特征，我们还不完全了解调节这一过程的细胞机制。我们的数据， 目前的文献表明，线粒体功能是由赖氨酸乙酰化，翻译后 使用燃料衍生的乙酰辅酶A作为底物的修饰。我们最近发现GCN 5L 1是第一个 线粒体乙酰转移酶机制的组成部分，并表明GCN 5L 1介导的乙酰化 控制体外线粒体生物能量学。本提案的目的是了解GCN 5L 1 乙酰化影响心脏中的线粒体生物能量学，并研究能量失调如何影响心脏中的线粒体生物能量学。 底物利用可导致线粒体功能障碍、心脏能量消耗和心力衰竭。我们将 通过解决以下问题实现这一目标：（1）GCN 5L 1如何控制脂肪酸氧化 在健康的心脏？(2)GCN 5L 1如何控制心力衰竭进展过程中的底物利用？(3)如何 GCN 5L 1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 在体内鼠心力衰竭模型和体外细胞培养研究中，结合代谢、蛋白质组学和 生物化学技术，以检查GCN 5L 1的生物学。我们希望这一系列的实验 提供了重要的线粒体能量底物调控的新见解，并将突出GCN 5L 1作为一个 在控制代谢燃料的选择，生物能量学和线粒体在心脏的周转的关键组成部分。

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.