Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism

John C. Schell, Dona R. Wisidagama, Claire Bensard, Helong Zhao, Peng Wei, Jason Tanner, Aimee Flores, Jerey Mohlman, Lise K. Sorensen, Christian S. Earl, Kristofor A. Olson, Ren Miao, T. Cameron Waller, Don Delker, Priyanka Kanth, Lei Jiang, Ralph J. DeBerardinis, Mary P. Bronner, Dean Y. Li, James E. CoxHeather R. Christofk, William E. Lowry, Carl S. Thummel, Jared Rutter

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Abstract

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells.

Original languageEnglish (US)
Pages (from-to)1027-1036
Number of pages10
JournalNature Cell Biology
Volume19
Issue number9
DOIs
StatePublished - Sep 1 2017

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Schell, J. C., Wisidagama, D. R., Bensard, C., Zhao, H., Wei, P., Tanner, J., Flores, A., Mohlman, J., Sorensen, L. K., Earl, C. S., Olson, K. A., Miao, R., Waller, T. C., Delker, D., Kanth, P., Jiang, L., DeBerardinis, R. J., Bronner, M. P., Li, D. Y., ... Rutter, J. (2017). Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Nature Cell Biology, 19(9), 1027-1036. https://doi.org/10.1038/ncb3593