Emanuel Berger
,
Technical University of Munich, Freising-Weihenstephan, BY, Germany
Detian Yuan
,
Helmholtz-Zentrum München, Institute of Virology, Munich, Germany
Nadine Waldschmitt
,
Technische Universität München, School of Life Sciences Weihenstephan, Chair of Nutrition and Immunology, Freising-Weihenstephan, Germany
Eva Rath
,
Technische Universität München, School of Life Sciences Weihenstephan, Chair of Nutrition and Immunology, Freising-Weihenstephan, Germany
Michael Allgäuer
,
Technische Universität München, Institute of Medical Microbiology, Immunology and Hygiene, Munich, Germany
Ori Staszewski
,
University of Freiburg, Institute of Neuropathology, Fribourg, Germany
Olivia Kober
,
Technische Universität München, Chair of Nutrition and Immunology, Freising-Weihenstephan, Germany
Elena Lobner
,
Technische Universität München, Chair of Nutrition and Immunology, Freising-Weihenstephan, Germany
Theresa Schöttl
,
Technische Universität München, Chair of Molecular Nutritional Medicine, Else Kröner-Fresenius Center, Freising-Weihenstephan, Germany
Marco Prinz
,
University of Freiburg, Institute of Neuropathology, Fribourg, Germany
Achim Weber
,
University Hospital Zurich, Institute of Surgical Pathology, Zurich, Switzerland
Markus Gerhard
,
Technische Universität München, München, Germany
Martin Klingenspor
,
Technische Universität München, ZIEL – Research Center for Nutrition and Food Sciences, Freising-Weihenstephan, Germany
Klaus-Peter Janssen
,
Technische Universität München, Department of Surgery, Munich, Germany
Mathias Heikenwälder
,
Helmholtz-Zentrum München, Institute of Virology, Munich, Germany
Dirk Haller
,
Technische Universität München, ZIEL Research Center for Nutrition and Food Sciences, Freising-Weihenstephan, Germany
Mitochondrial dysfunction contributes to metabolic and inflammatory pathologies. Heat shock protein 60 (HSP60), a mitochondrial unfolded protein response (mtUPR)-associated chaperone, is highly expressed in the intestinal epithelium under conditions of chronic inflammation. This study uses tissue-specific HSP60 knockout mouse models to investigate the impact of mitochondrial function on epithelial cell homeostasis.
Postnatal deletion of Hsp60 in the epithelium (Hsp60flox/floxXVillinCreERT2) activated hallmarks of MT-UPR, including the induction of Chop, mitochondrial protease ClpP and chaperone Grp75. Consistent with decreased expression levels of mitochondrial cytochrome c oxidase subunit I (mtCoxI) in the epithelium of Hsp60ΔIEC mice, mitochondrial respiration and ATP production were diminished in small intestinal crypt organoids upon tamoxifen-induced deletion of Hsp60. Mitochondrial dysfunction and MT-UPR induction in Hsp60ΔIEC mice was associated with a significant loss of epithelial stemness and proliferative capacity in the transit amplifying zone. In parallel, HSP60-deficient epithelial cells released WNT10a, WNT2b and RSPO1 and induced hyperproliferative responses in stem cell compartments with sporadic failure of Cre-mediated Hsp60 deletion. This stem cell hyperproliferation led to a massive alteration in epithelial morphology.
In conclusion, tissue-specific deletion of Hsp60 triggers mitochondrial dysfunction and loss of stemness. In response to the disruption of epithelial cell homeostasis, paracrine secretion of WNT-related signals activate hyperproliferation of residual stem cells that have escaped Hsp60 deletion.
