Integrative single-cell metabolomics and phenotypic profiling reveals metabolic heterogeneity of cellular oxidation and senescence

  • Nat Commun. 2025 Mar 20;16(1):2740. doi: 10.1038/s41467-025-57992-3.
Ziyi Wang  1 ,  Siyuan Ge  1 ,  Tiepeng Liao  1 ,  Man Yuan  1 ,  Wenwei Qian  1 ,  Qi Chen  1 ,  Wei Liang  1 ,  Xiawei Cheng  2 ,  Qinghua Zhou  3 ,  Zhenyu Ju  3 ,  Hongying Zhu  4  5  6  7 ,  Wei Xiong  8  9  10  11
Affiliations
  • 1. Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001, Hefei, China.
  • 2. School of Pharmacy, Optogenetics & Synthetic Biology Interdisciplinary Research Center, East China University of Science and Technology, 200237, Shanghai, China.
  • 3. Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Department of Developmental & Regenerative Medicine, College of Life Science and Technology, Jinan University, 510632, Guangzhou, Guangdong, China.
  • 4. Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001, Hefei, China. [email protected].
  • 5. Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, 230088, Hefei, China. [email protected].
  • 6. CAS Key Laboratory of Brain Function and Disease, 230026, Hefei, China. [email protected].
  • 7. Anhui Province Key Laboratory of Biomedical Aging Research, 230026, Hefei, China. [email protected].
  • 8. Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001, Hefei, China. [email protected].
  • 9. Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, 230088, Hefei, China. [email protected].
  • 10. CAS Key Laboratory of Brain Function and Disease, 230026, Hefei, China. [email protected].
  • 11. Anhui Province Key Laboratory of Biomedical Aging Research, 230026, Hefei, China. [email protected].
PMID: 40113759 DOI: 10.1038/s41467-025-57992-3
Abstract

Emerging evidence has unveiled heterogeneity in phenotypic and transcriptional alterations at the single-cell level during oxidative stress and senescence. Despite the pivotal roles of cellular metabolism, a comprehensive elucidation of metabolomic heterogeneity in cells and its connection with cellular oxidative and senescent status remains elusive. By integrating single-cell live imaging with mass spectrometry (SCLIMS), we establish a cross-modality technique capturing both metabolome and oxidative level in individual cells. The SCLIMS demonstrates substantial metabolomic heterogeneity among cells with diverse oxidative levels. Furthermore, the single-cell metabolome predicted heterogeneous states of cells. Remarkably, the pre-existing metabolomic heterogeneity determines the divergent cellular fate upon oxidative insult. Supplementation of key metabolites screened by SCLIMS resulted in a reduction in cellular oxidative levels and an extension of C. elegans lifespan. Altogether, SCLIMS represents a potent tool for integrative metabolomics and phenotypic profiling at the single-cell level, offering innovative approaches to investigate metabolic heterogeneity in cellular processes.

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