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Spatial-fluxomics provides a subcellular-compartmentalized view of reductive glutamine metabolism in cancer cells

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  • Won Dong Lee

    (Technion)

  • Dzmitry Mukha

    (Technion)

  • Elina Aizenshtein

    (Technion)

  • Tomer Shlomi

    (Technion
    Technion
    Technion)

Abstract

The inability to inspect metabolic activities within subcellular compartments has been a major barrier to our understanding of eukaryotic cell metabolism. Here, we describe a spatial-fluxomics approach for inferring metabolic fluxes in mitochondria and cytosol under physiological conditions, combining isotope tracing, rapid subcellular fractionation, LC-MS-based metabolomics, computational deconvolution, and metabolic network modeling. Applied to study reductive glutamine metabolism in cancer cells, shown to mediate fatty acid biosynthesis under hypoxia and defective mitochondria, we find a previously unappreciated role of reductive IDH1 as the sole net contributor of carbons to fatty acid biosynthesis under standard normoxic conditions in HeLa cells. In murine cells with defective SDH, we find that reductive biosynthesis of citrate in mitochondria is followed by a reversed CS activity, suggesting a new route for supporting pyrimidine biosynthesis. We expect this spatial-fluxomics approach to be a highly useful tool for elucidating the role of metabolic dysfunction in human disease.

Suggested Citation

  • Won Dong Lee & Dzmitry Mukha & Elina Aizenshtein & Tomer Shlomi, 2019. "Spatial-fluxomics provides a subcellular-compartmentalized view of reductive glutamine metabolism in cancer cells," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09352-1
    DOI: 10.1038/s41467-019-09352-1
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    Cited by:

    1. Mahmoud A. Bassal & Saumya E. Samaraweera & Kelly Lim & Brooks A. Benard & Sheree Bailey & Satinder Kaur & Paul Leo & John Toubia & Chloe Thompson-Peach & Tran Nguyen & Kyaw Ze Ya Maung & Debora A. Ca, 2022. "Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Ruohong Wang & Yandong Yin & Jingshu Li & Hongmiao Wang & Wanting Lv & Yang Gao & Tangci Wang & Yedan Zhong & Zhiwei Zhou & Yuping Cai & Xiaoyang Su & Nan Liu & Zheng-Jiang Zhu, 2022. "Global stable-isotope tracing metabolomics reveals system-wide metabolic alternations in aging Drosophila," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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