title: Mitochondrial function controls intestinal epithelial stemness and proliferation.
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.
authors: Technische Universität München, Chair of Nutrition and Immunology, 85350 Freising-Weihenstephan, Germany.
authors: Emanuel
authors: E
authors: Berger
authors: Technische Universität München, Chair of Nutrition and Immunology, 85350 Freising-Weihenstephan, Germany.
authors: Eva
authors: E
authors: Rath
authors: Helmholtz-Zentrum München, Institute of Virology, 85764 Neuherberg, Germany.
authors: Detian
authors: D
authors: Yuan
authors: Technische Universität München, Chair of Nutrition and Immunology, 85350 Freising-Weihenstephan, Germany.
authors: Nadine
authors: N
authors: Waldschmitt
authors: Technische Universität München, Chair of Nutrition and Immunology, 85350 Freising-Weihenstephan, Germany.
authors: Sevana
authors: S
authors: Khaloian
authors: Technische Universität München, Institute of Medical Microbiology, Immunology and Hygiene, 81675 Munich, Germany.
authors: Michael
authors: M
authors: Allgäuer
authors: University of Freiburg, Institute of Neuropathology, Freiburg 79106, Germany.
authors: Ori
authors: O
authors: Staszewski
authors: Technische Universität München, Chair of Nutrition and Immunology, 85350 Freising-Weihenstephan, Germany.
authors: Elena M
authors: EM
authors: Lobner
authors: Technische Universität München, Chair of Molecular Nutritional Medicine, Else Kröner-Fresenius Center, 85350 Freising-Weihenstephan, Germany.
authors: Theresa
authors: T
authors: Schöttl
authors: Technische Universität München, Department of Nutritional Physiology, 85350 Freising-Weihenstephan, Germany.
authors: Pieter
authors: P
authors: Giesbertz
authors: Technische Universität München, Chair of Nutrition and Immunology, 85350 Freising-Weihenstephan, Germany.
authors: Olivia I
authors: OI
authors: Coleman
authors: University of Freiburg, Institute of Neuropathology, Freiburg 79106, Germany.|BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
authors: Marco
authors: M
authors: Prinz
authors: University Hospital Zurich, Institute of Surgical Pathology, 8091 Zurich, Switzerland.
authors: Achim
authors: A
authors: Weber
authors: Technische Universität München, Institute of Medical Microbiology, Immunology and Hygiene, 81675 Munich, Germany.
authors: Markus
authors: M
authors: Gerhard
authors: Technische Universität München, Chair of Molecular Nutritional Medicine, Else Kröner-Fresenius Center, 85350 Freising-Weihenstephan, Germany.|Technische Universität München, ZIEL-Institute for Food &Health, 85350 Freising-Weihenstephan, Germany.
authors: Martin
authors: M
authors: Klingenspor
authors: Technische Universität München, Department of Surgery, 81675 Munich, Germany.
authors: Klaus-Peter
authors: KP
authors: Janssen
authors: Helmholtz-Zentrum München, Institute of Virology, 85764 Neuherberg, Germany.|German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, 69120 Heidelberg, Germany.
authors: Mathias
authors: M
authors: Heikenwalder
authors: Technische Universität München, Chair of Nutrition and Immunology, 85350 Freising-Weihenstephan, Germany.|Technische Universität München, ZIEL-Institute for Food &Health, 85350 Freising-Weihenstephan, Germany.
authors: Dirk
authors: D
authors: Haller
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D018834:Chaperonin 60 / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007413:Intestinal Mucosa / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018834:Chaperonin 60; C557066:Hspd1 protein, mouse; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D051153:Wnt Proteins; C484143:Wnt10a protein, mouse; D051742:Transcription Factor CHOP