Mitochondrial function — gatekeeper of intestinal epithelial cell homeostasis

Abstract

The intestinal epithelium is a multicellular interface in close proximity to a dense microbial milieu that is completely renewed every 3–5 days. Pluripotent stem cells reside at the crypt, giving rise to transient amplifying cells that go through continuous steps of proliferation, differentiation and finally anoikis (a form of programmed cell death) while migrating upwards to the villus tip. During these cellular transitions, intestinal epithelial cells (IECs) possess distinct metabolic identities reflected by changes in mitochondrial activity. Mitochondrial function emerges as a key player in cell fate decisions and in coordinating cellular metabolism, immunity, stress responses and apoptosis. Mediators of mitochondrial signalling include molecules such as ATP and reactive oxygen species and interrelate with pathways such as the mitochondrial unfolded protein response (MT-UPR) and AMP kinase signalling, in turn affecting cell cycle progression and stemness. Alterations in mitochondrial function and MT-UPR activation are integral aspects of pathologies, including IBD and cancer. Mitochondrial signalling and concomitant changes in metabolism contribute to intestinal homeostasis and regulate IEC dedifferentiation–differentiation programmes in the context of diseases, suggesting that mitochondrial function as a cellular checkpoint critically contributes to disease outcome. This Review highlights mitochondrial function and MT-UPR signalling in epithelial cell stemness, differentiation and lineage commitment and illustrates mitochondrial function in intestinal diseases.

Key points

  • The intestinal epithelium is a constantly renewing monolayer of cells undergoing continuous steps of proliferation, differentiation and finally cell death, representing an excellent model system to study stem cell regulation.

  • Intestinal epithelial cells (IECs) are key players in intestinal diseases such as IBD and colorectal cancer (CRC), constituting a dynamic interface between microbiota and host.

  • Mitochondrial function and metabolism determine and regulate IEC properties, such as differentiation status and proliferation.

  • Mitochondrial unfolded protein response (MT-UPR) coordinates mitochondrial function, metabolism and cellular phenotype and is activated in various diseases, including IBD and CRC.

  • MT-UPR might act as a sensor of the luminal and host environment, orchestrating epithelial tissue responses.

  • Determining the proliferative and regenerative capacity of IECs, the MT-UPR constitutes an attractive target for future therapeutic approaches for intestinal diseases.

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Fig. 1: Overview of different branches of mammalian MT-UPR signalling.
Fig. 2: Mitochondrial function of IEC along the crypt–villus axis.
Fig. 3: Interrelated aspects of IEC properties, mitochondrial function and intestinal disease mechanisms.

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Rath, E., Moschetta, A. & Haller, D. Mitochondrial function — gatekeeper of intestinal epithelial cell homeostasis. Nat Rev Gastroenterol Hepatol 15, 497–516 (2018). https://doi.org/10.1038/s41575-018-0021-x

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