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Mitochondrial function controls intestinal epithelial stemness and proliferation

Author

Listed:
  • 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
    BIOSS Centre for Biological Signalling Studies, University of Freiburg)

  • 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
    Technische Universität München, ZIEL—Institute for Food & Health)

  • Klaus-Peter Janssen

    (Technische Universität München)

  • Mathias Heikenwalder

    (Helmholtz-Zentrum München, Institute of Virology
    German Cancer Research Center (DKFZ))

  • Dirk Haller

    (Technische Universität München, Chair of Nutrition and Immunology
    Technische Universität München, ZIEL—Institute for Food & Health)

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.

Suggested Citation

  • 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 Pr, 2016. "Mitochondrial function controls intestinal epithelial stemness and proliferation," Nature Communications, Nature, vol. 7(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13171
    DOI: 10.1038/ncomms13171
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    Cited by:

    1. Shuting Li & Chia-Wen Lu & Elia C. Diem & Wang Li & Melanie Guderian & Marc Lindenberg & Friederike Kruse & Manuela Buettner & Stefan Floess & Markus R. Winny & Robert Geffers & Hans-Hermann Richnow &, 2022. "Acetyl-CoA-Carboxylase 1-mediated de novo fatty acid synthesis sustains Lgr5+ intestinal stem cell function," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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