Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.
John C. Schell,Dona R. Wisidagama,Claire L. Bensard,Helong Zhao,Peng Wei,Jason M. Tanner,Aimee Flores,Jeffrey Mohlman,Lise K. Sorensen,Christian S. Earl,Kristofor A. Olson,Ren Miao,T. Cameron Waller,Don A. Delker,Priyanka Kanth,Lei Jiang,Lei Jiang,Ralph J. DeBerardinis,Mary P. Bronner,Dean Y. Li,James E. Cox,Heather R. Christofk,William E. Lowry,Carl S. Thummel,Jared Rutter +24 more
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TLDR
It is demonstrated that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells and to understand the role this transition from glycolysis to pyruVate oxidation plays in stem cell maintenance and differentiation.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.read more
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The multifaceted contributions of mitochondria to cellular metabolism.
TL;DR: This Review discusses how mitochondria catabolize nutrients for energy, generate biosynthetic precursors for macromolecules, compartmentalize metabolites for the maintenance of redox homeostasis and function as hubs for metabolic waste management.
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The impact of cellular metabolism on chromatin dynamics and epigenetics.
TL;DR: The biochemical and genetic principles of how metabolism can influence chromatin biology and epigenetics are described, the functional roles of this interplay in developmental and cancer biology are discussed, and future directions in this rapidly emerging area are presented.
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Anatomy and Physiology of the Digestive Tract of Drosophila melanogaster
TL;DR: This review summarizes the current knowledge of both the formation and function of the Drosophila melanogaster digestive tract, with a major focus on its main digestive/absorptive portion: the strikingly adaptable adult midgut.
Journal ArticleDOI
Fasting activates Fatty Acid Oxidation to enhance intestinal stem cell function during homeostasis and aging
Maria M. Mihaylova,Chia-Wei Cheng,Chia-Wei Cheng,Amanda Q. Cao,Surya Tripathi,Miyeko D. Mana,Miyeko D. Mana,Khristian E. Bauer-Rowe,Khristian E. Bauer-Rowe,Monther Abu-Remaileh,Laura Clavain,Aysegul Erdemir,Aysegul Erdemir,Caroline A. Lewis,Elizaveta Freinkman,Audrey S. Dickey,Albert R. La Spada,Yanmei Huang,George W. Bell,Vikram Deshpande,Peter Carmeliet,Pekka Katajisto,Pekka Katajisto,David M. Sabatini,Ömer H. Yilmaz,Ömer H. Yilmaz,Ömer H. Yilmaz +26 more
TL;DR: It is shown that a 24 hr fast augments intestinal stem cell (ISC) function in young and aged mice by inducing a fatty acid oxidation (FAO) program and that pharmacological activation of this program mimics many effects of fasting.
Journal ArticleDOI
Mitochondria as central regulators of neural stem cell fate and cognitive function
TL;DR: How mitochondria can serve as signalling organelles that modify the fate of stem cells in the brain is discussed, which has major implications in physiological and pathological conditions.
References
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Journal ArticleDOI
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.
Toshiro Sato,Robert G.J. Vries,Hugo J. Snippert,Marc van de Wetering,Nick Barker,Daniel E. Stange,Johan H. van Es,Arie Abo,Pekka Kujala,Peter J. Peters,Hans Clevers +10 more
TL;DR: It is concluded that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.
Journal ArticleDOI
Identification of stem cells in small intestine and colon by marker gene Lgr5
Nick Barker,Johan H. van Es,Jeroen Kuipers,Pekka Kujala,Maaike van den Born,Miranda Cozijnsen,Andrea Haegebarth,Jeroen Korving,Harry Begthel,Peter J. Peters,Hans Clevers +10 more
TL;DR: The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers, suggesting that it represents the stem cell of the small intestine and colon.
Journal ArticleDOI
Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts
Toshiro Sato,Johan H. van Es,Hugo J. Snippert,Daniel E. Stange,Robert G.J. Vries,Maaike van den Born,Nick Barker,Noah F. Shroyer,Marc van de Wetering,Hans Clevers +9 more
TL;DR: It is concluded that Lgr5 stem cells compete for essential niche signals provided by a specialized daughter cell, the Paneth cell, in colon crypts, and co-culturing of sorted stem cells with Paneth cells markedly improves organoid formation.
Journal ArticleDOI
Towards a knowledge-based Human Protein Atlas
Mathias Uhlén,Per Oksvold,Linn Fagerberg,Emma Lundberg,Kalle Jonasson,Mattias Forsberg,Martin Zwahlen,Caroline Kampf,Kenneth Wester,Sophia Hober,Henrik Wernérus,Lisa Björling,Fredrik Pontén +12 more
TL;DR: The analysis here suggests that state stem cell funding programs are sufficiently large and established that simply ending the programs, at least in the absence of substantial investment in the field by other funding sources, could have deleterious effects.