Mitochondrial function controls intestinal epithelial stemness and proliferation

Emanuel Berger, Eva Rath, Detian Yuan, Nadine Waldschmitt, Sevana Khaloian, Michael Allgäuer, Ori Staszewski, Elena M. Lobner, Theresa Schöttl, Pieter Giesbertz, Olivia I. Coleman, Marco Prinz, Achim Weber, Markus Gerhard, Martin Klingenspor, Klaus-Peter Janssen, Mathias Heikenwalder and Dirk Haller ()
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Emanuel Berger: Technische Universität München, Chair of Nutrition and Immunology
Eva Rath: Technische Universität München, Chair of Nutrition and Immunology
Detian Yuan: Helmholtz-Zentrum München, Institute of Virology
Nadine Waldschmitt: Technische Universität München, Chair of Nutrition and Immunology
Sevana Khaloian: Technische Universität München, Chair of Nutrition and Immunology
Michael Allgäuer: Technische Universität München, Institute of Medical Microbiology, Immunology and Hygiene
Ori Staszewski: University of Freiburg, Institute of Neuropathology
Elena M. Lobner: Technische Universität München, Chair of Nutrition and Immunology
Theresa Schöttl: Technische Universität München, Chair of Molecular Nutritional Medicine, Else Kröner-Fresenius Center
Pieter Giesbertz: Technische Universität München
Olivia I. Coleman: Technische Universität München, Chair of Nutrition and Immunology
Marco Prinz: University of Freiburg, Institute of Neuropathology
Achim Weber: University Hospital Zurich, Institute of Surgical Pathology
Markus Gerhard: Technische Universität München, Institute of Medical Microbiology, Immunology and Hygiene
Martin Klingenspor: Technische Universität München, Chair of Molecular Nutritional Medicine, Else Kröner-Fresenius Center
Klaus-Peter Janssen: Technische Universität München
Mathias Heikenwalder: Helmholtz-Zentrum München, Institute of Virology
Dirk Haller: Technische Universität München, Chair of Nutrition and Immunology

Nature Communications, 2016, vol. 7, issue 1, 1-17

Abstract: Abstract Control of intestinal epithelial stemness is crucial for tissue homeostasis. Disturbances in epithelial function are implicated in inflammatory and neoplastic diseases of the gastrointestinal tract. Here we report that mitochondrial function plays a critical role in maintaining intestinal stemness and homeostasis. Using intestinal epithelial cell (IEC)-specific mouse models, we show that loss of HSP60, a mitochondrial chaperone, activates the mitochondrial unfolded protein response (MT-UPR) and results in mitochondrial dysfunction. HSP60-deficient crypts display loss of stemness and cell proliferation, accompanied by epithelial release of WNT10A and RSPO1. Sporadic failure of Cre-mediated Hsp60 deletion gives rise to hyperproliferative crypt foci originating from OLFM4+ stem cells. These effects are independent of the MT-UPR-associated transcription factor CHOP. In conclusion, compensatory hyperproliferation of HSP60+ escaper stem cells suggests paracrine release of WNT-related factors from HSP60-deficient, functionally impaired IEC to be pivotal in the control of the proliferative capacity of the stem cell niche.

Date: 2016
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DOI: 10.1038/ncomms13171

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