P053 Mitochondrial dysfunction impairs epithelial proliferative control and stemness in the intestinal crypts
E. Berger*1, D. Yuan2, N. Waldschmitt1, E. Rath1, M. Allgäuer3, O. Staszewski4, O. Kober1, E. Lobner1, T. Schöttl5, M. Prinz4, A. Weber6, M. Gerhard3, M. Klingenspor5, K.-P. Janssen7, M. Heikenwälder2, D. Haller1
1Technische Universität München, ZIEL - Research Center for Nutrition and Food Sciences, Chair of Nutrition and Immunology, Freising-Weihenstephan, Germany, 2Helmholtz-Zentrum München, Institute of Virology, Munich, Germany, 3Technische Universität München, Institute of Medical Microbiology, Immunology and Hygiene, Munich, Germany, 4University of Freiburg, Institute of Neuropathology, Fribourg, Germany, 5Technische Universität München, Chair of Molecular Nutritional Medicine, Else Kröner-Fresenius Center & Research Center for Nutrition and Food Sciences, Freising-Weihenstephan, Germany, 6University Hospital Zurich, Institute of Surgical Pathology, Zurich, Switzerland, 7Technische Universität München, Department of Surgery, Munich, Germany
Heat shock protein 60 (HSP60), a mitochondrial unfolded protein response (mtUPR)-associated chaperone, is highly expressed in intestinal epithelial cells (IEC) of mouse models with chronic inflammation and in patients with inflammatory bowel disease (IBD).
This study investigates the impact of mitochondrial function and mtUPR on epithelial homeostasis using novel tissue-specific Hsp60 knockout mouse models.
Postnatal induction of HSP60 deficiency in IEC (Hsp60flox/floxXVillinCreERT2-Tg) caused substantial aberrations in cryptal architecture of the proximal and less in the distal intestine. MT-UPR induction in HSP60-deficient IEC was associated with an abrogated expression of Ki67, Lgr5 and Olfm4, indicating a significant loss of epithelial stemness and proliferative capacity. Mitochondria in the HSP60-deficient epithelium showed a decreased expression of functional markers like the mitochondrial encoded subunit I of the cytochrome c oxidase (mtCoxI) complex as part of the respiratory chain. Tamoxifen-induced deletion of Hsp60 in small intestinal crypt organoids ex vivo diminished mitochondrial respiration and ATP production, suggesting a role of mitochondrial function in regulating crypt homeostasis. Consistent with the release of growth factors WNT10a, WNT2b and RSPO1 from HSP60-deficient IEC, hyperproliferative stem cell nodules developed in regions with sporadic failure of Cre-mediated Hsp60 deletion, strongly supporting a role for HSP60 in regulating the proliferative response of the epithelium.
In conclusion, tissue-specific deletion of Hsp60 disrupts epithelial cell homeostasis, largely independent of an inflammation-associated pathology. HSP60 deficiency in the intestinal epithelium triggers mtUPR and affects mitochondrial function, leading to an impaired proliferative response and a loss of stemness.