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

基本信息

批准号：
8721002
负责人：
Angelical S. Martin
金额：
$ 3.24万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8721002
关键词：
Ablation Acetylation Affect Aging Animals Area Binding 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 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 Protein Binding 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 public health relevance reconstitution research study therapy development

项目摘要

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）是生物学中必不可少的辅助因子，在许多细胞过程中起着多种作用。这些角色包括激活参与多种关键途径的关键酶，包括代谢和ATP产生。 ISC的组装通过核心ISC生物发生蛋白ISD11，ISCU，NSF1和Frataxin（FXN）的高度协调活性发生。这些核心蛋白的缺陷或缺乏会导致能量代谢受损，并表现出毁灭性的人类疾病，例如：弗里德里希共济失调的患者因FXN的水平不足而导致的弗里德里希共济失调患者的致命心力衰竭（HF）；以及缺乏ISCU患者的严重肌病。因此，必须深入了解ISC生物发生的过程对于了解该途径在人类疾病中的作用是必要的。然而，ISC生物发生调节的分子基础知之甚少。该项目的长期目标是更好地了解ISC生物发生调节，特别是在ISC生物发生如何与代谢和能量需求的变化相协调的情况下。赖氨酸乙酰化及其通过线粒体NAD+依赖性蛋白脱乙酰基酶Sirtuin 3（SIRT3）的调节正在成为能量稳态的主要调节剂。 SIRT3的脱乙酰基酶活性调节了许多参与ATP产生的代谢酶。最近的研究表明，SIRT3脱乙酰基酶的活性对于维持心脏组织中的ATP水平是必要的，以表达SIRT3在调节线粒体能量代谢中的重要作用。蛋白质组学研究将几种ISC生物发生蛋白鉴定为SIRT3调节的候选物，但是乙酰化在调节这种关键的药水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是调节线粒体能量稳态的一种机制，正如脂肪酸代谢途径和TCA循环所证明的那样。我们确定了一种以这种方式是强大候选者的核心ISC生物发生蛋白。我们的中心假设是，SIRT3乙酰化和脱乙酰基化对于调节酶促功能至关重要，从而以新颖的方式调节ISC生物发生。我们将通过追求以下两个具体目的来检验中心假设：（1）确定乙酰化对ISC生物发生涉及的酶的生化作用，以及；（2）确定SIRT3在体内调节ISC生物发生中的作用。我们的发现将为未开发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，我们的发现可以确定一种新的策略，以开发能源生产受损的疾病（例如HF和与ISC相关的疾病）的疗法。