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

项目摘要 心力衰竭是一项重大的公共卫生挑战。心脏新陈代谢受损是 心力衰竭进展的基本机制。心脏组织的表达谱研究 揭示心力衰竭中转录因子网络被抑制的激活，包括过氧化物酶体 增殖因子激活受体-γ共激活因子1α(pGC-1α)，其主要调节因子 线粒体生物发生和氧化磷酸化，导致许多代谢基因 降低监管。与心力衰竭不同的是，耐力运动通过 上调PGC-1α的表达，使其处于运动诱导的中心 适应性反应。调控PGC-1α表达的分子机制 人们对运动或病理性压力导致心力衰竭知之甚少。线粒体的功能是 也受线粒体蛋白翻译后修饰的调控。我们小组确认了将军 氨基酸合成5-样蛋白(GCN5L1)作为第一乙酰基转移酶蛋白的调控 线粒体动态乙酰化调节脂肪酸氧化。GCN5L1在心脏疾病中的作用 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 GCN5L1在人和小鼠衰竭心脏和心脏GCN5L1基因敲除中的表达降低 小鼠(CGCN5L1 KO)表现为经主动脉缩窄后心力衰竭进展加剧 (TAC)，强调GCN5L1在心力衰竭中发挥重要作用。超越核-线粒体 单向交流，新出现的证据表明线粒体也可以逆行 通过代谢中间体、反应性氧化物种或多肽向细胞核发出信号以重新编程 代谢基因转录。GCN5L1主要定位于线粒体，在线粒体中缺失。 原子核。在我们的初步数据中，运动诱导的pGC-1α上调在cGCN5L1中被钝化 与WT对照组相比，TACcGCN5L1KO小鼠PGC-1α表达也降低 心脏与TAC WT小鼠比较。这些发现表明GCN5L1在 控制pGC-1α的表达。在这项提案中，利用我们的新型遗传老鼠模型，我们将 验证GCN5L1通过以下途径在增强心脏生物能量方面发挥关键作用的假设 运动或心力衰竭时pGC-1α信号的逆行激活。三 具体目的是：1)验证GCN5L1诱导PGC-1α表达的假设 通过逆行激活p38 MAPK对压力超负荷的反应，2)检验假设 GCN5L1通过逆行组蛋白诱导压力超负荷反应中PGC-1α的表达 H3K27，3)乙酰化以检验GCN5L1支配耐力适应性反应的假设 运动通过逆行激活PGC-1α信号。

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.