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; Dirk Haller

doi:10.1038/ncomms13171

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, Dirk Haller

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133 Scopus citations

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.

Original language	English
Article number	13171
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13171
State	Published - 27 Oct 2016

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Berger, E., Rath, E., Yuan, D., Waldschmitt, N., Khaloian, S., Allgäuer, M., Staszewski, O., Lobner, E. M., Schöttl, T., Giesbertz, P., Coleman, O. I., Prinz, M., Weber, A., Gerhard, M., Klingenspor, M., Janssen, K. P., Heikenwalder, M., & Haller, D. (2016). Mitochondrial function controls intestinal epithelial stemness and proliferation. Nature Communications, 7, Article 13171. https://doi.org/10.1038/ncomms13171

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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.",

author = "Emanuel Berger and Eva Rath and Detian Yuan and Nadine Waldschmitt and Sevana Khaloian and Michael Allg{\"a}uer and Ori Staszewski and Lobner, {Elena M.} and Theresa Sch{\"o}ttl and Pieter Giesbertz and Coleman, {Olivia I.} and Marco Prinz and Achim Weber and Markus Gerhard and Martin Klingenspor and Janssen, {Klaus Peter} and Mathias Heikenwalder and Dirk Haller",

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year = "2016",

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doi = "10.1038/ncomms13171",

language = "English",

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Berger, E, Rath, E, Yuan, D, Waldschmitt, N, Khaloian, S, Allgäuer, M, Staszewski, O, Lobner, EM, Schöttl, T, Giesbertz, P, Coleman, OI, Prinz, M, Weber, A, Gerhard, M , Klingenspor, M, Janssen, KP, Heikenwalder, M & Haller, D 2016, 'Mitochondrial function controls intestinal epithelial stemness and proliferation', Nature Communications, vol. 7, 13171. https://doi.org/10.1038/ncomms13171

TY - JOUR

T1 - Mitochondrial function controls intestinal epithelial stemness and proliferation

AU - Berger, Emanuel

AU - Rath, Eva

AU - Yuan, Detian

AU - Waldschmitt, Nadine

AU - Khaloian, Sevana

AU - Allgäuer, Michael

AU - Staszewski, Ori

AU - Lobner, Elena M.

AU - Schöttl, Theresa

AU - Giesbertz, Pieter

AU - Coleman, Olivia I.

AU - Prinz, Marco

AU - Weber, Achim

AU - Gerhard, Markus

AU - Klingenspor, Martin

AU - Janssen, Klaus Peter

AU - Heikenwalder, Mathias

AU - Haller, Dirk

PY - 2016/10/27

Y1 - 2016/10/27

N2 - 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.

AB - 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.

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SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

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Mitochondrial function controls intestinal epithelial stemness and proliferation

Abstract

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