Role of Carnitine Acetyltransferase in Mitochondrial and Metabolic Function

肉碱乙酰转移酶在线粒体和代谢功能中的作用

基本信息

批准号：
9039045
负责人：
DEBORAH M MUOIO
金额：
$ 49.87万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9039045
关键词：
Ablation Acetyl Coenzyme A Acetylation Acyl Coenzyme A Affect Aging Area Binding Biological Markers Blood Blood Glucose Branched-Chain Amino Acids Buffers Carbon Carnitine Carnitine O-Acetyltransferase Catabolism Data Deacetylase Deacetylation Diabetes Mellitus Diet Energy Metabolism Enzymes Event Exercise Tolerance Fatty Acids Functional disorder Funding Genetic Glucose Health Homeostasis Human Knockout Mice Laboratories Levocarnitine Link Lysine Mediating Membrane Metabolic Metabolic Control Metabolic Diseases Micronutrients Mitochondria Mitochondrial Matrix Mitochondrial Proteins Modeling Mus Muscle Muscle Mitochondria Nature Niacinamide Nutraceutical Nutrient Obese Mice Obesity Outcome Overnutrition Physiological Positioning Attribute Post-Translational Protein Processing Process Protein Acetylation Proteins Proteomics Reporting Research Rodent Role Site Skeletal Muscle Specimen Stress Sulfhydryl Compounds System Testing Tissues Work acyl group acylcarnitine amino group blood glucose regulation combinatorial enzyme activity in vivo loss of function metabolic abnormality assessment metabolomics mitochondrial dysfunction novel therapeutic intervention public health relevance stem targeted treatment tool

项目摘要

DESCRIPTION (provided by applicant): Our work in the area of mitochondrial function, energy homeostasis and metabolomics has led us to discover a remarkably strong association between adverse cardiometabolic outcomes and tissue/blood levels of acylcarnitine conjugates. These metabolites derive from acyl-CoA intermediates of fuel catabolism and permit mitochondrial export of excess carbons. Our working model positions acylcarnitines as biomarkers of mitochondrial stress and vehicles of stress relief. To test this hypothesis we have been studying the metabolic and physiological importance of carnitine acetyltransferase (CrAT), the mitochondrial matrix enzyme that converts acetyl-CoA and other short chain acyl-CoA species to their membrane permeant acylcarnitine counterparts. During the previous funding cycle we determined that the acyl group buffering capacity of CrAT is necessary for normal fuel selection, glucose control and exercise tolerance. One of the most exciting and potentially important discoveries we made is that genetic ablation of CrAT in mouse skeletal muscle increases tissue concentrations of acetyl-CoA and exacerbates diet-induced acetylation of mitochondrial proteins. Lysine acetylation (AcK) is reversible post-translational protein modification (PTM) in which a two carbon acetyl group is covalently bound to the e-amino group of a lysine residue. This PTM is found prominently on mitochondrial proteins and excessive AcK has been linked to metabolic disease in mice lacking sirtuin 3 (SIRT3), the principal mitochondrial-localized deacetylase enzyme that removes acetyl groups from specific lysine residues. Our preliminary data suggest AcK can occur non- enzymatically when the mitochondrial pool of acetyl-CoA expands. The proposed project applies state-of-the-art proteomics and metabolomics approaches to test our hypothesis that CrAT and SIRT3 function cooperatively to oppose mitochondrial carbon stress, and that coexisting insufficiencies in the function of these enzymes contribute to metabolic dysregulation in the context of metabolic disease. Because CrAT and SIRT3 depend on availability of essential micronutrient substrates, L-carnitine and nicotinamide, we will also determine whether a new combinatorial nutraceutical strategy that targets the two systems simultaneously might confer additive or perhaps synergetic metabolic benefits when administered to obese rodents.

描述（由适用提供）：我们在线粒体功能，能量稳态和代谢组学领域的工作使我们发现了不良心脏代谢结果与组织/血液水平之间存在很强的相关性。这些代谢产物衍生出燃料分解代谢的中间体，并允许线粒体出口过多的碳。我们的工作模型将酰基肉碱定位为线粒体应力和应力缓解措施的生物标志物。为了检验这一假设，我们一直在研究肉碱乙酰基转移酶（CRAT）的代谢和物理重要性，即转化乙酰基-COA和其他短链乙酰辅酶A到其膜乙酰丙基苯甲烷对手的线粒体基质酶。在上一个融资周期中，我们确定crat的酰基基团缓冲能力对于正常的燃料选择，葡萄糖控制和运动耐受性是必要的。我们做出的最令人兴奋和潜在的最重要发现之一是，小鼠骨骼肌的遗传消融会增加乙酰-COA的组织浓度，并加剧饮食诱导的线粒体蛋白的乙酰化。赖氨酸乙酰化（ACK）是可逆的翻译后蛋白质修饰（PTM），其中两个碳乙酰基团共价与赖氨酸残基的E-Amino组结合。该PTM在线粒体蛋白上是显着发现的，并且超过ACK与缺乏SIRTUIN 3（SIRT3）的小鼠的代谢性疾病有关，这是主要的线粒体 - 位细胞 - 脱乙酰基酶，从而将乙酰基团从特定原因中移除。我们的初步数据表明，当乙酰辅酶A的线粒体池扩展时，ACK可能非酶促发生。拟议的项目采用了最先进的蛋白质组学和代谢组学方法来检验我们的假设，即crat和sirt3合作起作用与线粒体碳应激相对，并且在这些酶的功能中共存的不足，在代谢性疾病的背景下导致代谢失调有助于这些酶的功能。由于Crat和Sirt3取决于必需的微量营养素底物，L-肉碱和烟酰胺的可用性，因此我们还将确定针对这两种系统的新组合营养策略是在给肥胖的啮齿动物时是否会导致两种系统的新型组合营养策略。