Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA; Department of Medicine, Division of Geriatrics, Duke University Medical Center, Durham, NC 27710, USA.
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA; Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA.
Cell Metab. 2023 Jun 6;35(6):1038-1056.e8. doi: 10.1016/j.cmet.2023.03.016. Epub 2023 Apr 14.
Even-chain acylcarnitine (AC) metabolites, most of which are generated as byproducts of incomplete fatty acid oxidation (FAO), are viewed as biomarkers of mitochondrial lipid stress attributable to one or more metabolic bottlenecks in the β-oxidation pathway. The origins and functional implications of FAO bottlenecks remain poorly understood. Here, we combined a sophisticated mitochondrial phenotyping platform with state-of-the-art molecular profiling tools and multiple two-state mouse models of respiratory function to uncover a mechanism that connects AC accumulation to lipid intolerance, metabolic inflexibility, and respiratory inefficiency in skeletal muscle mitochondria. These studies also identified a short-chain carbon circuit at the C4 node of FAO wherein reverse flux of glucose-derived acetyl CoA through medium-chain ketothiolase enhances lipid tolerance and redox stability in heart mitochondria by regenerating free CoA and NAD. The findings help to explain why diminished FAO capacity, AC accumulation, and metabolic inflexibility are tightly linked to poor health outcomes.
偶数链酰基辅酶 A（AC）代谢物，大多数是不完全脂肪酸氧化（FAO）的副产物，被认为是线粒体脂质应激的生物标志物，归因于β-氧化途径中的一个或多个代谢瓶颈。FAO 瓶颈的起源和功能意义仍知之甚少。在这里，我们结合了复杂的线粒体表型平台和最先进的分子分析工具以及多种呼吸功能的两状态小鼠模型，揭示了一种机制，将 AC 积累与脂质不耐受、代谢灵活性差和骨骼肌线粒体呼吸效率低下联系起来。这些研究还确定了 FAO 的 C4 节点的短链碳循环，其中葡萄糖衍生的乙酰辅酶 A 通过中链酮硫解酶的反向通量增强了心脏线粒体的脂质耐受性和氧化还原稳定性，通过再生游离辅酶 A 和 NAD。这些发现有助于解释为什么 FAO 能力下降、AC 积累和代谢灵活性差与健康状况不佳密切相关。
