@article{5147097525ca445c867cd2de7b8923f3,
title = "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.",
author = "Schell, {John C.} and Wisidagama, {Dona R.} and Claire Bensard and Helong Zhao and Peng Wei and Jason Tanner and Aimee Flores and Jerey Mohlman and Sorensen, {Lise K.} and Earl, {Christian S.} and Olson, {Kristofor A.} and Ren Miao and Waller, {T. Cameron} and Don Delker and Priyanka Kanth and Lei Jiang and DeBerardinis, {Ralph J.} and Bronner, {Mary P.} and Li, {Dean Y.} and Cox, {James E.} and Christofk, {Heather R.} and Lowry, {William E.} and Thummel, {Carl S.} and Jared Rutter",
note = "Funding Information: We thank B. Edgar (University of Utah, USA) for stocks and reagents, C. Micchelli (Washington University School of Medicine, USA) for providing the Notch RNAi line, K. Beebe for helpful advice and comments on the Drosophila intestinal studies, G. Lam for establishing the Drosophila MPC overexpression strain, O. Yilmaz and D. Sabatini for assistance and insight into intestinal stem cell metabolism, D. Tantin for critiques and comments, members of the Rutter laboratory for assistance and advice, J. O{\textquoteright}Shea, R. Orbus and C. DeHeer for assistance with NanoString, W. Swiatek for mouse assistance, ARUP Institute for Clinical and Experimental Pathology, and S. R. Tripp and E. Hammond for histology; L. Nikolova at the University of Utah Electron Microscopy Core Laboratory performed electron microscopy; mass spectrometry analysis was performed at the Mass Spectrometry and Proteomics Core Facility at the University of Utah. Mass spectrometry equipment was obtained through NCRR Shared Instrumentation Grant no. 1 S10 RR020883-01, 1 S10 RR025532-01A1, NIH 1 S10OD021505-01 (J.E.C.) and the Diabetes and Metabolism Center at the University of Utah. This study was conducted with support from the Biorepository and Molecular Pathology Shared Resource supported by the Cancer Center Support Grant awarded to the Huntsman Cancer Institute by the National Cancer Institute of the National Institutes of Health. Nanostring transcript analysis utilized the Molecular Diagnostics Section of the Biorepository and Molecular Pathology Shared Resource and was supported by the National Cancer Institute of the National Institutes of Health under Award Number P30CA042014 (the content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH). J. Marvin at the University of Utah Flow Cytometry Facility carried out flow sorting (National Cancer Institute through Award Number 5P30CA042014-24, National Center for Research Resources of the National Institutes of Health under Award Number 1S10RR026802-01). Funding was also provided by HHMI (J.R.), Treadwell (J.R.) and RO1GM094232 (to J.R. and C.S.T.). J.C.S. was supported by an NIH Developmental Biology Training Grant (5T32 HD07491) and a University of Utah Graduate Research Fellowship. D.R.W. was supported by a University of Utah Graduate Research Fellowship. Publisher Copyright: {\textcopyright} 2017 Macmillan Publishers Limited, part of Springer Nature.",
year = "2017",
month = sep,
day = "1",
doi = "10.1038/ncb3593",
language = "English (US)",
volume = "19",
pages = "1027--1036",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "9",
}