The Role of Acetylation in the Regulation Iron-Sulfur Cluster Biogenesis and Mito

乙酰化在调节铁硫簇生物合成和有丝分裂中的作用

• 批准号: 9090197
• 负责人: Angelical S. Martin
• 金额: $ 3.33万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9090197
• 关键词: Ablation; Acetylation; Affect; Aging; Animals; Area; Binding; Binding Proteins; Biochemical; Biochemistry; Biogenesis; Biological Assay; Biology; Cardiac; Cardiomyopathies; Cell physiology; Characteristics; Chemicals; Citric Acid Cycle; Core Protein; Critical Pathways; Deacetylase; Deacetylation; Defect; Discipline; Disease; Disease Progression; Energy Metabolism; Enzymes; Exposure to; Fatty Acids; Friedreich Ataxia; Goals; Grx5 protein; Health; Heart; Heart Diseases; Heart failure; Hereditary Disease; Homeostasis; Human; Individual; Iron; Iron Overload; Iron Regulatory Protein 1; Iron-Binding Proteins; Knock-out; Life; Lysine; Maintenance; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Methods; Mission; Mitochondria; Molecular; Molecular Chaperones; Molecular and Cellular Biology; Monitor; Morbidity - disease rate; Mus; Myocardial; Myopathy; Pathway interactions; Patients; Physiological; Physiology; Play; Post-Translational Protein Processing; Process; Production; Protein Acetylation; Proteins; Proteomics; Regulation; Research; Role; Science; Site; Sulfur; Sulofenur; Testing; Therapeutic; Tissues; Training; cofactor; deprivation; frataxin; human disease; in vivo; insight; iron metabolism; mortality; mouse model; novel; overexpression; primary outcome; protein protein interaction; reconstitution; research study; therapy development

DESCRIPTION (provided by applicant): Iron-Sulfur clusters (ISCs) are essential cofactors in biology that serve a variety of roles in many cellular processes. These roles include activating key enzymes involved in several critical pathways, including metabolism and ATP production. Assembly of ISCs occurs through the highly coordinated activities of core ISC biogenesis proteins ISD11, ISCU, Nsf1, and Frataxin (FXN). Defect or deficiency of these core proteins results in impaired energy metabolism and manifests in devastating human diseases such as: the fatal heart failure (HF) in patients with Friedreich's Ataxia caused by insufficient levels of he FXN; and the severe myopathy in patients deficient in ISCU. Therefore, a deeper understanding of the process of ISC biogenesis is necessary to understand the role this pathway plays in human disease. The molecular underpinnings of ISC biogenesis regulation, however, remain poorly understood. The long-term goal of this project is to better understand ISC biogenesis regulation, particularly in how ISC biogenesis is coordinated in with changes in metabolism and energy demands. Lysine acetylation and its regulation through the mitochondrial NAD+-dependent protein deacetylase Sirtuin 3 (SIRT3) is emerging as a major regulator of energy homeostasis. SIRT3's deacetylase activity modulates many metabolic enzymes involved in ATP production. Recent studies have demonstrated that SIRT3 deacetylase activity is necessary for maintaining ATP levels in cardiac tissue-underscoring the important role of SIRT3 in regulating mitochondrial energy metabolism. Proteomic studies identified several ISC biogenesis proteins as candidates of regulation by SIRT3, but the role of acetylation in regulating this critical celluar process is unknown. We predict that acetylation of proteins in the ISC biogenesis pathway serves as a mechanism of regulating mitochondrial energy homeostasis, as has been demonstrated for fatty- acid metabolic pathways and the TCA cycle. We identified one core ISC biogenesis protein that is a strong candidate in this manner. Our central hypothesis is that acetylation and deacetylation by SIRT3 is critical in modulating enzymatic function, thereby regulating ISC biogenesis in a novel manner. We will test our central hypothesis by pursuing the following two specific aims: (1) determine the biochemical role of acetylation on the enzymes involved in ISC biogenesis, and; (2) determine the role of SIRT3 in regulating ISC biogenesis in vivo. Our findings will provide novel insights into an unexplored area of science: a crosstalk between acetylation and ISC biogenesis, and its role in energy homeostasis. Additionally, our findings could identify a new strategy for the development of therapies for diseases of impaired energy production, such as HF, and ISC-related disorders.

描述（由申请人提供）：铁硫簇（ISC）是生物学中重要的辅助因子，在许多细胞过程中发挥多种作用。这些作用包括激活参与多个关键途径的关键酶，包括代谢和 ATP 产生。 ISC 的组装是通过核心 ISC 生物合成蛋白 ISD11、ISCU、Nsf1 和 Frataxin (FXN) 的高度协调活动来进行的。这些核心蛋白的缺陷或缺乏会导致能量代谢受损，并导致毁灭性的人类疾病，例如：由于 FXN 水平不足而导致弗里德赖希共济失调患者致命的心力衰竭 (HF)； ISCU 不足的患者会出现严重的肌病。因此，有必要更深入地了解 ISC 生物发生过程，以了解该途径在人类疾病中的作用。然而，ISC 生物发生调节的分子基础仍然知之甚少。该项目的长期目标是更好地了解 ISC 生物发生调控，特别是 ISC 生物发生如何与代谢和能量需求的变化相协调。赖氨酸乙酰化及其通过线粒体 NAD+ 依赖性蛋白脱乙酰酶 Sirtuin 3 (SIRT3) 的调节正在成为能量稳态的主要调节因子。 SIRT3 的脱乙酰酶活性调节许多参与 ATP 生成的代谢酶。最近的研究表明，SIRT3 脱乙酰酶活性对于维持心脏组织中的 ATP 水平是必要的——强调了 SIRT3 在调节线粒体能量代谢中的重要作用。蛋白质组学研究确定了几种 ISC 生物发生蛋白作为 SIRT3 调节的候选蛋白，但乙酰化在调节这一关键细胞过程中的作用尚不清楚。我们预测 ISC 生物发生途径中蛋白质的乙酰化可作为调节线粒体能量稳态的机制，正如脂肪酸代谢途径和 TCA 循环所证明的那样。我们确定了一种核心 ISC 生物发生蛋白，它是这种方式的有力候选者。我们的中心假设是 SIRT3 的乙酰化和脱乙酰化对于调节酶功能至关重要，从而以一种新的方式调节 ISC 生物发生。我们将通过追求以下两个具体目标来检验我们的中心假设：（1）确定乙酰化对 ISC 生物发生所涉及的酶的生化作用； (2)确定SIRT3在体内调节ISC生物合成中的作用。我们的研究结果将为未探索的科学领域提供新的见解：乙酰化和 ISC 生物发生之间的串扰及其在能量稳态中的作用。此外，我们的研究结果可以确定一种新策略，用于开发治疗能量产生受损疾病（例如心力衰竭和 ISC 相关疾病）的疗法。