Mechanisms of lipid-induced bioenergetic stress in muscle

摘要 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 组织/血液水平的酰基肉毒碱（AC）共轭物。这些代谢产物来源于酰基辅酶A 燃料催化剂的中间体，并允许线粒体输出过量的碳。过去 十年来，我们的实验室一直热衷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？目前的建议旨在检验AC积累反映了一种 脂肪酸氧化（FAO）途径中的瓶颈，减少线粒体的力量， 效率这一预测源于通过应用一种新的 线粒体诊断平台由我们的实验室在上一个资助周期开发。 简而言之，我们的测定作为体外“压力测试”，评估给定的 由碳底物的特定混合物提供燃料的线粒体群体响应于分级的 充满活力的挑战。我们一直在将这个平台与基于质谱的 代谢组学、蛋白质组学和13 C代谢通量分析，以评估线粒体重塑 以及呼吸功率和效率的相应变化， 营养和遗传策略。新的令人兴奋的发现表明， 反映了线粒体FAO途径中关键的热力学脆弱性，从而为 作为生物能量压力的信号，在通往受损的生物能量学和即将到来的 组织/器官衰竭此外，我们的初步研究表明，线粒体居住在未经训练的 骨骼肌和衰竭的心脏特别容易受到这种脂质引起的“交通堵塞”的影响; 酮是唯一能够绕过路障，以捍卫细胞能量学的设置， 代谢压力。因此，我们还旨在检验酮氧化起作用的假设， 在允许已知的有益的线粒体和代谢适应方面发挥重要作用， 发生在间歇性禁食的反应中。

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.