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：
9249032
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/9249032
关键词：
Ablation Acetyl Coenzyme A Acetylation Acyl Coenzyme A Affect Aging Area 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 Impairment 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 Nutritional Obese Mice Obesity Outcome Overnutrition Physiological Positioning Attribute Post-Translational Protein Processing Process Protein Acetylation Proteins Proteomics Reporting Research Rodent Role Sirtuins Site Skeletal Muscle Specimen Stress Sulfhydryl Compounds System Testing Tissues Work acyl group acylcarnitine alkalinity 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（由申请人提供）：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不良心脏代谢结果与酰基肉碱缀合物的组织/血液水平之间存在令人惊讶的强烈关联。 CoA 是分解代谢的中间体，允许线粒体输出多余的碳。我们的工作模型将酰基肉碱定位为线粒体应激的生物标志物和缓解应激的工具。为了检验这一假设，我们一直在研究肉碱乙酰转移酶 (CrAT) 的代谢和生理重要性，CrAT 是一种线粒体基质酶，可将乙酰辅酶 A 和其他短链酰基辅酶 A 种类转化为其膜渗透性酰基肉碱成员。确定 CrAT 的酰基缓冲能力对于正常的燃料选择、葡萄糖控制和运动耐量是必需的，我们所做的最令人兴奋和潜在重要的发现之一是遗传。小鼠骨骼肌组织中 CrAT 的消除会增加乙酰辅酶 A 的浓度，并恶化饮食诱导的线粒体蛋白乙酰化。赖氨酸乙酰化 (AcK) 是可逆的翻译后蛋白修饰 (PTM)，其中两个碳乙酰基共价结合。赖氨酸残基的 e-氨基基团主要存在于线粒体蛋白上，过量的 AcK 与代谢疾病有关。缺乏 Sirtuin 3 (SIRT3) 的小鼠，这是一种主要的线粒体定位脱乙酰酶，可去除特定赖氨酸残基上的乙酰基。我们的初步数据表明，当线粒体乙酰辅酶 A 库扩展时，AcK 可以非酶促方式发生。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 协同发挥作用来对抗线粒体碳应激，以及这些酶的功能共存不足会导致代谢疾病中的代谢失调，因为 CrAT 和 SIRT3 依赖于必需微量营养素底物、左旋肉碱和烟酰胺的可用性，因此我们还将确定是否有一种针对该疾病的新组合营养保健策略。当对肥胖啮齿类动物施用时，这两个系统同时可能会带来附加的或可能协同的代谢益处。