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: 10189058
• 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/10189058
• 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; Histones; Hospitalization; Human; Impairment; Knockout Mice; Learning Skill; Lysine; MAP Kinase Gene; Mediating; Mediator of activation protein; Mentors; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; Modification; Molecular; Mus; Neonatal; Nuclear; Oxidative Phosphorylation; PPAR gamma; Pathologic; Peptides; Physicians; Play; Pluripotent Stem Cells; 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; constriction; cost; endurance exercise; fatty acid oxidation; genome editing; heart cell; heart metabolism; hepatic gluconeogenesis; improved; interest; knock-down; mortality; mouse model; myocyte-specific enhancer-binding factor 2; new therapeutic target; novel; overexpression; p38 Mitogen Activated Protein Kinase; pressure; 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 心力衰竭是一个主要的公共卫生挑战。心脏代谢受损是 心力衰竭进展的基本机制。心脏组织的表达分析 揭示了心力衰竭中的转录因子网络激活的反映，包括过氧组合体 扩散剂激活的受体伽马共振剂1α（PGC-1α），主调节剂 线粒体生物发生和氧化磷酸化，导致许多代谢基因 下调。与心力衰竭相反，耐力运动通过 PGC-1α表达的上调，将该分子放置在运动诱导的中心 自适应反应。响应PGC-1α表达的分子机制响应于 导致心力衰竭的运动或病理压力知之甚少。线粒体功能是 也受线粒体蛋白的翻译后修饰调节。我们的小组确定了一般 控制氨基酸合成5样1（GCN5L1）作为第一个负责的乙酰转移酶蛋白 动态线粒体乙酰化调节脂肪酸氧化。 GCN5L1在心脏中的作用 能量调节和心力衰竭在很大程度上未知。在我们的新初步数据中，我们发现 人和鼠失败的心脏和心脏GCN5L1敲除中GCN5L1的表达降低 小鼠（CGCN5L1 KO）在经际狭窄后显示出加重的心力衰竭进展 （TAC），强调GCN5L1在心力衰竭中起着重要作用。超越核原则 单向沟通，新兴证据表明，线粒体也可以进行逆行 通过代谢中间体，反应性氧化物或Petides向细胞核发出信号，以重新编程 代谢基因转录。 GCN5L1主要位于线粒体，在 核。在我们的初步数据中，练习引起的PGC-1α上调在CGCN5L1中被钝化 KO小鼠相对于WT对照，PGC-1α表达也降低了TAC CGCN5L1 KO小鼠 与TAC WT小鼠相比。这些发现表明GCN5L1在 控制PGC-1α表达。在此提案中，利用我们新颖的遗传小鼠模型，我们将 检验GCN5L1在增强心脏生物能源方面起关键作用的假设 运动或心力衰竭发育过程中PGC-1α信号传导的逆行激活。三 提出了具体目的：1）测试GCN5L1影响PGC-1α表达的假设 通过p38 mapk的逆行激活对压力超负荷的响应，2）检验以下假设： GCN5L1通过逆行组蛋白诱导PGC-1α表达响应压力超负荷 H3K27的乙酰化，3）测试了GCN5L1控制耐力反应的假设 通过PGC-1α信号传导的逆行激活进行锻炼。