Mechanisms of lipid-induced bioenergetic stress in muscle

摘要 我们在线粒体功能、能量动态平衡和代谢组学领域的工作使我们 发现心脏代谢不良结果与 组织/血液中酰基肉碱(AC)结合物的水平。这些代谢物来源于酰基辅酶A 燃料分解代谢的中间产物，并允许线粒体输出多余的碳。为了过去 十年来，我们的实验室一直致力于回答一个关键问题：什么是 这个AC信号告诉我们线粒体和代谢之间的相互作用 疾病？目前的提议旨在检验交流积聚反映出 脂肪酸氧化(FAO)途径中的瓶颈，它降低了线粒体的能力和 效率。这一预测源于通过应用一种新的 线粒体诊断平台是我们实验室在前一个资助周期中开发的。 简单地说，我们的分析就像是一种体外“压力测试”，用来评估一个给定的 线粒体的数量，由特定的碳底物混合物提供燃料，对分级的 充满活力的挑战。我们一直在将这个平台与基于质谱学的 代谢组学、蛋白质组学和~(13)C代谢流分析评价线粒体重构 以及呼吸功率和效率的相应变化，以响应各种 营养和遗传操作。新的令人兴奋的发现表明，交流积聚 反映了线粒体粮农组织途径中的一个关键热力学脆弱性，从而为 作为生物能量压力的信号，在向生物能量学妥协的途中，并即将到来 组织/器官衰竭。此外，我们的初步研究表明，线粒体驻留在未经训练的 骨骼肌和衰竭的心脏特别容易受到这种由脂质引起的“交通堵塞”的影响； 酮是唯一能够绕过障碍，在环境中保护细胞能量学的 新陈代谢压力。因此，我们也致力于验证酮氧化起作用的假设。 在允许有益的线粒体和已知的代谢适应中的重要作用 发生于对间歇性禁食的反应。

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.