小柯机器人

美国杜克大学Deborah M. Muoio研究小组发现，丙酮酸支持的通量通过中链酮硫醇酶促进心脏和骨骼肌线粒体的脂质耐受性。相关论文于2023年4月14日在线发表在《细胞—代谢》杂志上。

研究人员将一个复杂的线粒体表型平台与最先进的分子分析工具和多个呼吸功能的双状态小鼠模型结合起来，并发现了一种将偶链酰基肉碱（AC）积累与脂质不耐受、代谢不灵活和骨骼肌线粒体呼吸效率低下联系起来的机制。这些研究还确定了不完全脂肪酸氧化（FAO） C4节点的短链碳回路，其中葡萄糖衍生的乙酰CoA通过中链酮硫醇酶的反向流动，通过再生游离CoA和NAD⁺来增强心脏线粒体的脂质耐受性和氧化还原稳定性。这些发现有助于解释为什么FAO能力减弱、AC积累和代谢不灵活与健康状况不佳密切相关。

据了解，AC代谢物的大部分是作为不FAO的副产品产生的，被视为线粒体脂质压力的生物标志物，这归因于β-氧化途径中的一个或多个代谢瓶颈。FAO瓶颈的起源和功能影响仍然知之甚少。

附：英文原文

Title: Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles

Author: Timothy R. Koves, Guo-Fang Zhang, Michael T. Davidson, Alec B. Chaves, Scott B. Crown, Jordan M. Johnson, Dorothy H. Slentz, Paul A. Grimsrud, Deborah M. Muoio

Issue&Volume: 2023-04-14

Abstract: Even-chain acylcarnitine (AC) metabolites, most of which are generated as byproductsof incomplete fatty acid oxidation (FAO), are viewed as biomarkers of mitochondriallipid stress attributable to one or more metabolic bottlenecks in the β-oxidationpathway. The origins and functional implications of FAO bottlenecks remain poorlyunderstood. Here, we combined a sophisticated mitochondrial phenotyping platform withstate-of-the-art molecular profiling tools and multiple two-state mouse models ofrespiratory function to uncover a mechanism that connects AC accumulation to lipidintolerance, metabolic inflexibility, and respiratory inefficiency in skeletal musclemitochondria. These studies also identified a short-chain carbon circuit at the C4node of FAO wherein reverse flux of glucose-derived acetyl CoA through medium-chainketothiolase enhances lipid tolerance and redox stability in heart mitochondria byregenerating free CoA and NAD+. The findings help to explain why diminished FAO capacity, AC accumulation, and metabolicinflexibility are tightly linked to poor health outcomes.

DOI: 10.1016/j.cmet.2023.03.016

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00094-3

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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