Mechanisms of lipid-induced bioenergetic stress in muscle

脂质诱导肌肉生物能应激的机制

• 批准号: 10162581
• 负责人: DEBORAH M MUOIO
• 金额: $ 59万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162581
• 关键词: ATP Hydrolysis; Acute; Acyl Coenzyme A; Age; Aging; Area; Bioenergetics; Biological Assay; Biological Markers; Blood; Blood Glucose; Butyrates; Carbon; Cardiac; Cardiometabolic Disease; Catabolic Process; Catabolism; Clinical; Complex; Consumption; Diabetes Mellitus; Diagnostic; Disease; Electron Transport; Electrons; Energy Metabolism; Energy Transfer; Enzymes; Event; Exercise Tolerance; Exercise stress test; Fasting; Fatty Acids; Free Energy; Functional disorder; Grant; Health; Heart; Heart Mitochondria; Heart failure; Hereditary Disease; Homeostasis; Human; Impairment; In Vitro; Institutes; Intermittent fasting; Ketones; Kinetics; Laboratories; Link; Lipids; Mass Spectrum Analysis; Mediator of activation protein; Membrane Potentials; Metabolic; Metabolic Diseases; Metabolic stress; Metabolism; Methods; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Modeling; Mole the mammal; Molecular; Molecular Profiling; Mus; Muscle; Muscle Mitochondria; Myocardial dysfunction; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Normal Cell; Nutrient; Obesity; Organ; Organ failure; Outcome; Oxidation-Reduction; Oxidoreductase; Pathway interactions; Phosphorylation; Physiological; Physiology; Play; Population; Post-Translational Protein Processing; Potential Energy; Prediabetes syndrome; Process; Proteomics; Regimen; Reporting; Research Personnel; Resistance; Role; Route; Signal Transduction; Skeletal Muscle; Stress; Stress Tests; Technology; Testing; Thermodynamics; Tissues; Work; acylcarnitine; age related; base; cancer cachexia; cardiometabolism; diagnostic assay; diagnostic platform; exercise intolerance; fatty acid oxidation; insight; long chain fatty acid; metabolomics; mitochondrial dysfunction; multiple omics; multiplex assay; novel therapeutic intervention; nutrition related genetics; oxidation; phosphoproteomics; respiratory; response; stem; tool

Abstract 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 (AC) conjugates. These metabolites derive from acyl-CoA intermediates of fuel catabolism and permit mitochondrial export of excess carbons. For the past decade, our laboratory has remained keenly committed to answering a crucial question: What is this AC signature telling us about the interplay between mitochondria and metabolic disease? The current proposal aims to test the hypothesis that AC accumulation reflects a bottleneck in the fatty acid oxidation (FAO) pathway that diminishes mitochondrial power and efficiency. This prediction stems from unique insights gained via the application of a new mitochondrial diagnostics platform developed by our laboratory during the previous grant cycle. In simple terms, our assays serve as an in vitro “stress test” that evaluates how well a given population of mitochondria, fueled by specific mixtures of carbon substrates, responds to a graded energetic challenge. We have been combining this platform with mass spectrometry-based metabolomics, proteomics and 13C metabolic flux analysis to evaluate mitochondrial remodeling and corresponding changes in respiratory power and efficiency in response to a variety of nutritional and genetic maneuvers. New and exciting findings suggest that AC accumulation reflects a critical thermodynamic vulnerability in the mitochondrial FAO pathway, and thereby serves as a signal of bioenergetic stress, en route to compromised bioenergetics and impending tissue/organ failure. Moreover, our preliminary studies suggest mitochondria resident in untrained skeletal muscles and failing hearts are especially vulnerable to this lipid-induced “traffic jam”; and that ketones are uniquely able to circumvent the roadblock to defend cellular energetics in settings of metabolic stress. Accordingly, we also aim to test the hypothesis that ketone oxidation plays an essential role in permitting the salutary mitochondrial and metabolic adaptations known to occur in response to regimens of intermittent fasting.

抽象的 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（AC）结合物的组织/血液水平。这些代谢物衍生出酰基辅酶A 燃料分解代谢的中间体并允许线粒体出口过多的碳。过去 十年，我们的实验室一直致力于回答一个关键问题：什么是 此AC签名告诉我们线粒体与代谢之间的相互作用 疾病？当前的提案旨在检验AC积累反映A的假设 脂肪酸氧化（FAO）途径的瓶颈，可降低线粒体和 效率。这种预测源于通过应用新的独特见解获得的独特见解 线粒体诊断平台由我们的实验室在上一个赠款周期中开发。 简而 线粒体的种群在碳底物的特定混合物的推动下对分级响应 充满活力的挑战。我们一直将这个平台与质谱基于质谱的结合 代谢组学，蛋白质组学和13C代谢通量分析，以评估线粒体重塑 以及响应各种呼吸能力和效率的相应变化 营养和遗传操作。新令人兴奋的发现表明AC积累 反映线粒体粮农组织途径中的关键热力学脆弱性，从而提供 作为生物能力压力的信号，在损害生物能和即将来临的途中 组织/器官衰竭。此外，我们的初步研究表明未经训练的线粒体居民 骨骼肌肉和失败的心脏特别容易受到这种脂质引起的“交通拥堵”的影响。和 酮具有独特的能力，能够绕过障碍在环境中捍卫蜂窝能量 代谢压力。彼此之间，我们还旨在检验酮氧化作用的假设 允许有益的线粒体和代谢适应性的重要作用 响应间歇性禁食方案而发生。