Journal Article

Mitochondrial function controls intestinal epithelial stemness and proliferation

Waldschmitt, Nadine, Schöttl, Theresa, Lobner, Elena M., Klingenspor, Martin, Prinz, Marco, Coleman, Olivia I., Yuan, Detian, Allgäuer, Michael, Khaloian, Sevana, Haller, Dirk, Heikenwalder, Mathias, Weber, Achim, Berger, Emanuel, Staszewski, Ori, Rath, Eva, Giesbertz, Pieter, Gerhard, Markus, Janssen, Klaus-Peter

2016

Overview

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. It is unclear what role mitochondrial function plays in maintaining intestinal epithelial cell (IEC) homeostasis. Here, the authors deplete a mitochondrial chaperone, heat shock protein 60 (HSP60) in IEC and observe a loss of stemness and cell proliferation, and suggest this is accompanied by a compensatory release of WNT-related factors.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/100 / 13/106 / 13/51 / 14 / 14/34 / 38 / 38/39 / 631/532/2437 / 631/80/642/333/1465 / 631/80/86/2368 / 64/60 / Animals / Cancer / Cell cycle / Cell Proliferation / Chaperonin 60 - genetics / Chaperonin 60 - metabolism / Embryonic Stem Cells - cytology / Embryonic Stem Cells - metabolism / Female / Gastrointestinal tract / Gene Expression Regulation, Developmental / Homeostasis / Humanities and Social Sciences / Immunology / Inflammatory bowel disease / Intestinal Mucosa - cytology / Intestinal Mucosa - embryology / Intestinal Mucosa - metabolism / Kinases / Metabolism / Mice, Inbred BALB C / Mice, Inbred C57BL / Mice, Inbred Strains / Mice, Knockout / Mice, Transgenic / Mitochondria - metabolism / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / multidisciplinary / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Pathogenesis / Proteins / Science / Science (multidisciplinary) / Stem cells / Transcription Factor CHOP - genetics / Transcription Factor CHOP - metabolism / Transcription factors / Unfolded Protein Response - genetics / Wnt Proteins - genetics / Wnt Proteins - metabolism