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Nat Cell Biol. 2017 Sep;19(9):1027-1036. doi: 10.1038/ncb3593. Epub 2017 Aug 14.

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

Author information

1
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
2
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
3
Department of Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
4
Eli and Edythe Broad Center for Regenerative Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
5
Department of Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, California 90095, USA.
6
Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
7
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
8
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
9
Department of Molecular and Cellular Endocrinology, Beckman Research Institute at City of Hope, Duarte, California 91010, USA.
10
Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
11
Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.

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.

PMID:
28812582
PMCID:
PMC6137334
DOI:
10.1038/ncb3593
[Indexed for MEDLINE]
Free PMC Article

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