The mitochondrial UPR regulator ATF5 promotes intestinal barrier function via control of the satiety response

Date

2022-12-15

Authors

Chamseddine, Douja
Mahmud, Siraje A.
Westfall, Aundrea K.
Castoe, Todd A.
Berg, Rance E.
Pellegrino, Mark W.

ORCID

0000-0002-2934-382X (Berg, Rance)

Journal Title

Journal ISSN

Volume Title

Publisher

Elsevier B.V.

Abstract

Organisms use several strategies to mitigate mitochondrial stress, including the activation of the mitochondrial unfolded protein response (UPR(mt)). The UPR(mt) in Caenorhabditis elegans, regulated by the transcription factor ATFS-1, expands on this recovery program by inducing an antimicrobial response against pathogens that target mitochondrial function. Here, we show that the mammalian ortholog of ATFS-1, ATF5, protects the host during infection with enteric pathogens but, unexpectedly, by maintaining the integrity of the intestinal barrier. Intriguingly, ATF5 supports intestinal barrier function by promoting a satiety response that prevents obesity and associated hyperglycemia. This consequently averts dysregulated glucose metabolism that is detrimental to barrier function. Mechanistically, we show that intestinal ATF5 stimulates the satiety response by transcriptionally regulating the gastrointestinal peptide hormone cholecystokinin, which promotes the secretion of the hormone leptin. We propose that ATF5 protects the host from enteric pathogens by promoting intestinal barrier function through a satiety-response-mediated metabolic control mechanism.

Description

Citation

Chamseddine, D., Mahmud, S. A., Westfall, A. K., Castoe, T. A., Berg, R. E., & Pellegrino, M. W. (2022). The mitochondrial UPR regulator ATF5 promotes intestinal barrier function via control of the satiety response. Cell reports, 41(11), 111789. https://doi.org/10.1016/j.celrep.2022.111789

Rights

© 2022 The Author(s).

License

Attribution 4.0 International (CC BY 4.0)