The Role of GCN5L1 Mediated Mitochondria to Nucleus Retrograde Cardiac Metabolism Reprogramming in Exercise and Heart Failure

GCN5L1 介导的线粒体对运动和心力衰竭中细胞核逆行心脏代谢重编程的作用

• 批准号: 10600019
• 负责人: Manling Zhang
• 金额: $ 16.05万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600019
• 关键词: ATF2 gene; Acetyl Coenzyme A; Acetylation; Acetyltransferase; Amino Acids; Attenuated; Award; Bioenergetics; Biogenesis; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Nucleus; ChIP-seq; Chemicals; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Data; Development; Down-Regulation; Enzymes; Epigenetic Process; Exercise; Expression Profiling; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Hand; Heart; Heart failure; Histone Acetylation; Hospitalization; Human; Impairment; Knockout Mice; Learning Skill; Lysine; MAP Kinase Gene; Mediating; Mediator; Mentors; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; Modification; Molecular; Mus; Neonatal; Nuclear; Oxidative Phosphorylation; PPAR gamma; Pathologic; Peptides; Phosphorylation; Physicians; Play; Positioning Attribute; Post-Translational Protein Processing; Preparation; Prevalence; Process; Proteins; Public Health; Rattus; Regulation; Research; Role; Scientist; Signal Transduction; Small Interfering RNA; Stress; Technology; Testing; Tissues; Transcription Coactivator; United States; Up-Regulation; Work; aorta constriction; cofactor; cost; endurance exercise; fatty acid oxidation; gene repression; genome editing; heart cell; heart metabolism; hepatic gluconeogenesis; improved; induced pluripotent stem cell; interest; knock-down; mortality; mouse model; myocyte-specific enhancer-binding factor 2; new therapeutic target; novel; overexpression; p38 Mitogen Activated Protein Kinase; pressure; programs; response; therapeutic target; tool; transcription factor

PROJECT ABSTRACT Heart failure is a major public health challenge. Impaired cardiac metabolism is one of the fundamental mechanisms underlying heart failure progression. Expression profiling of cardiac tissues reveals repressed transcription factor network activation in heart failure, including Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), the master regulator of mitochondrial biogenesis and oxidative phosphorylation, resulting in many metabolic genes downregulation. In contrast to heart failure, endurance exercise enhances cardiac energetics through the upregulation of the PGC-1α expression, placing this molecule at the center of the exercise-induced adaptive response. The molecular mechanisms governing the expression of PGC-1α in response to exercise or pathological stress leading to heart failure are poorly understood. Mitochondrial function is also regulated by post-translational modifications of mitochondrial proteins. Our group identified General Control of Amino-Acid Synthesis 5-like 1 (GCN5L1) as the first acetyltransferase protein responsible for dynamic mitochondrial acetylation regulating fatty acid oxidation. The role of GCN5L1 in cardiac energetics regulation and heart failure are largely unknown. In our new preliminary data, we found that GCN5L1 expression was decreased in human and murine failing hearts and cardiac GCN5L1 knockout mice (cGCN5L1 KO) displayed exacerbated heart failure progression following transaortic constriction (TAC), highlighting that GCN5L1 plays an important role in heart failure. Beyond nuclear-mitochondria one-way communication, emerging evidence show that mitochondria can also engage in retrograde signaling to the nucleus via metabolic intermediates, reactive oxidative species or peptides to reprogram metabolic gene transcription. GCN5L1 is predominantly located in mitochondria and is absent in the nucleus. In our preliminary data, the exercise induced PGC-1α upregulation was blunted in cGCN5L1 KO mice relative to WT controls, and PGC-1α expression was also decreased in TAC cGCN5L1 KO mice hearts compared to TAC WT mice. These findings suggest that GCN5L1 plays an important role in controlling PGC-1α expression. In this proposal, leveraging our novel genetic mouse model, we will test the hypothesis that GCN5L1 plays a critical role in enhancing cardiac bioenergetics through retrograde activation of PGC-1α signaling during exercise or heart failure development. Three specific aims are proposed: 1) To test the hypothesis that GCN5L1 induces PGC-1α expression in response to pressure overload through retrograde activation of p38 MAPK, 2) To test the hypothesis that GCN5L1 induces PGC-1α expression in response to pressure overload through retrograde histone acetylation at H3K27, 3) To test the hypothesis that GCN5L1 governs adaptive response to endurance exercise through retrograde activation of PGC-1α signaling.

项目摘要 心力衰竭是一个重大的公共卫生挑战。心脏代谢受损是 心力衰竭进展的基本机制。心脏组织的表达谱 揭示了心力衰竭中受抑制的转录因子网络激活，包括过氧化物酶体 增殖物激活受体γ辅激活因子1 α（PGC-1α）， 线粒体生物合成和氧化磷酸化，导致许多代谢基因 下调与心力衰竭相反，耐力运动通过增强心脏能量， PGC-1α表达的上调，将该分子置于运动诱导的 适应性反应PGC-1α表达的分子机制 运动或病理性应激导致心力衰竭的原因尚不清楚。线粒体功能是 也受线粒体蛋白的翻译后修饰的调节。我们的小组确定了将军 氨基酸合成的控制5-like 1（GCN 5L 1）作为第一个乙酰转移酶蛋白负责 动态线粒体乙酰化调节脂肪酸氧化。GCN 5L 1在心肌细胞凋亡中的作用 能量调节和心力衰竭在很大程度上是未知的。在我们新的初步数据中，我们发现， GCN 5L 1基因敲除在人和小鼠衰竭心脏中的表达降低 小鼠（cGCN 5L 1 KO）在经主动脉缩窄后显示心力衰竭进展加剧 (TAC)GCN 5L 1在心力衰竭中发挥重要作用。超越核-线粒体 单向通信，新的证据表明，线粒体也可以从事逆行 通过代谢中间体、反应性氧化物质或肽向细胞核发出信号以进行重编程 代谢基因转录GCN 5L 1主要位于线粒体中，在线粒体中不存在。 原子核在我们的初步数据中，运动诱导的PGC-1α上调在cGCN 5L 1 KO小鼠相对于WT对照，TAC cGCN 5L 1 KO小鼠中PGC-1α表达也降低 与TAC WT小鼠相比。这些发现表明，GCN 5L 1在以下方面发挥重要作用： 控制PGC-1α的表达。在这项提案中，利用我们新的遗传小鼠模型，我们将 测试GCN 5L 1在增强心脏生物能量学中起关键作用的假设， 运动或心力衰竭发展过程中PGC-1α信号传导的逆行激活。三 具体目标如下：1）验证GCN 5L 1诱导PGC-1α表达的假设， 通过p38 MAPK的逆行激活对压力超负荷的反应，2）为了检验以下假设， GCN 5L 1通过逆行组蛋白诱导PGC-1α表达对压力超负荷的反应 H3 K27处乙酰化，3）为了检验GCN 5L 1调控耐力适应性反应的假设， 运动通过PGC-1α信号传导的逆向激活。