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.
MeSH terms
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Acrylates / pharmacology
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Animals
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Anion Transport Proteins / antagonists & inhibitors
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Anion Transport Proteins / genetics
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Anion Transport Proteins / metabolism
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Cell Differentiation
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Cell Proliferation* / drug effects
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Cells, Cultured
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Drosophila melanogaster / cytology
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Drosophila melanogaster / metabolism*
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Genotype
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Glycolysis*
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Humans
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Intestinal Mucosa / metabolism*
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Intestines / cytology
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Intestines / drug effects
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Lactic Acid / metabolism
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Mice, Knockout
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Mitochondrial Membrane Transport Proteins / antagonists & inhibitors
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Mitochondrial Membrane Transport Proteins / genetics
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Mitochondrial Membrane Transport Proteins / metabolism
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Mitochondrial Proteins / metabolism
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Monocarboxylic Acid Transporters
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Phenotype
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Pyruvic Acid / metabolism*
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RNA Interference
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism
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Signal Transduction
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Stem Cells / drug effects
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Stem Cells / metabolism*
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Time Factors
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Tissue Culture Techniques
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Transfection
Substances
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Acrylates
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Anion Transport Proteins
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Drosophila Proteins
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Lgr5 protein, mouse
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MPC1 protein, Drosophila
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MPC1 protein, human
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MPC1 pyruvate carrier protein, mouse
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Proteins
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Monocarboxylic Acid Transporters
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Receptors, G-Protein-Coupled
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Lactic Acid
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2-cyano-3-(1-phenylindol-3-yl)acrylate
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Pyruvic Acid