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MetTracer:Global Stable-isotope Tracing Metabolomics Reveals System-wide Metabolic Alternations in Aging Drosophila


Introduction: 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. Yet, delineating system-wide metabolic homeostasis at the whole-organism level remains non-trivial. Here, we first developed an untargeted isotope tracing metabolomics technology, namely MetTracer, to trace the stable-isotope labeled metabolites globally. This technology leveraged the advantages of untargeted metabolomics and targeted extraction to track the isotopically labeled metabolites in living organisms with a metabolome-wide coverage. MetTracer enabled to simultaneously quantify the labeling patterns and extents of several hundreds of metabolites in one experiment. Performances of MetTracer were benchmarked and validated with other existing tools. We further employed Drosophila as a model organism for untargeted in vivo isotope tracing metabolomics and quantified the in vivo labeling rates and extents of hundreds of labeled metabolites. We demonstrated that MetTracer supported quantitative comparisons of metabolite labeling extents across different conditions and discovered a system-wide loss of metabolic coordination that impacted both intra- and inter-tissue metabolic homeostasis significantly in aging Drosophila. In particular, we discovered a metabolic rewiring model during aging, wherein glucose was metabolically channeled to serine metabolism and purine metabolism from glycolysis. In summary, global in vivo isotope tracing metabolomics enabled delineation of metabolic activities with a metabolome-wide coverage and unraveled the system-wide loss of metabolic homeostasis during aging.




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1. R. Wang, Y. Yin, J. Li, H. Wang, W. Lv, Y. Gao, T. Wang, Y. Zhong, Z. Zhou, Y. Cai, X. Su, N. Liu*, and Z.-J. Zhu*, Global Stable-isotope Tracing Metabolomics Reveals System-wide Metabolic Alternations in Aging DrosophilaNature Communications, 2022, 13: 3518. Web Link