Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 200032, Shanghai, People's Republic of China.
University of Chinese Academy of Sciences, 100049, Beijing, People's Republic of China.
Nat Commun. 2022 Jun 20;13(1):3518. doi: 10.1038/s41467-022-31268-6.
System-wide metabolic homeostasis is crucial for maintaining physiological functions of living organisms. Stable-isotope tracing metabolomics allows to unravel metabolic activity quantitatively by measuring the isotopically labeled metabolites, but has been largely restricted by coverage. Delineating system-wide metabolic homeostasis at the whole-organism level remains challenging. Here, we develop a global isotope tracing metabolomics technology to measure labeled metabolites with a metabolome-wide coverage. Using Drosophila as an aging model organism, we probe the in vivo tracing kinetics with quantitative information on labeling patterns, extents and rates on a metabolome-wide scale. We curate a system-wide metabolic network to characterize metabolic homeostasis and disclose a system-wide loss of metabolic coordinations that impacts both intra- and inter-tissue metabolic homeostasis significantly during Drosophila aging. Importantly, we reveal an unappreciated metabolic diversion from glycolysis to serine metabolism and purine metabolism as Drosophila aging. The developed technology facilitates a system-level understanding of metabolic regulation in living organisms.
系统代谢稳态对于维持生物的生理功能至关重要。稳定同位素示踪代谢组学通过测量同位素标记代谢物，可定量揭示代谢活性，但受覆盖范围的限制较大。在全生物体水平上描绘系统代谢稳态仍然具有挑战性。在此，我们开发了一种全局同位素示踪代谢组学技术，以在代谢组范围内测量标记代谢物。我们以果蝇作为衰老模型生物，利用该技术在代谢组范围内定量探测体内示踪动力学，包括标记模式、程度和速率的定量信息。我们构建了一个系统代谢网络，以表征代谢稳态，并揭示了系统代谢协调的丧失，这在果蝇衰老过程中对组织内和组织间的代谢稳态都有显著影响。重要的是，我们揭示了一种未被认识到的从糖酵解到丝氨酸代谢和嘌呤代谢的代谢转变。该技术促进了对生物体代谢调控的系统水平理解。
