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

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.

DOI: 10.1038/ncb3593

Cite this paper

@article{Schell2017ControlOI, title={Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism}, author={John C. Schell and Dona R. Wisidagama and Claire L. Bensard and Helong Zhao and Peng Wei and Jason Tanner and Aimee Flores and Jeffrey S Mohlman and L. Sorensen and Christian S Earl and Kristofor A Olson and Ren Miao and T Cameron Waller and Don A. Delker and Priyanka Kanth and Lei Jiang and Ralph J DeBerardinis and Mary P Bronner and Dean Y. Li and James E. Cox and Heather R Christofk and William E Lowry and Carl S Thummel and Jared Rutter}, journal={Nature Cell Biology}, year={2017}, volume={19}, pages={1027-1036} }