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Mitochondrial function and gastrointestinal diseases

Nature Reviews Gastroenterology & Hepatology (2024)Cite this article

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Abstract

Mitochondria are dynamic organelles that function in cellular energy metabolism, intracellular and extracellular signalling, cellular fate and stress responses. Mitochondria of the intestinal epithelium, the cellular interface between self and enteric microbiota, have emerged as crucial in intestinal health. Mitochondrial dysfunction occurs in gastrointestinal diseases, including inflammatory bowel diseases and colorectal cancer. In this Review, we provide an overview of the current understanding of intestinal epithelial cell mitochondrial metabolism, function and signalling to affect tissue homeostasis, including gut microbiota composition. We also discuss mitochondrial-targeted therapeutics for inflammatory bowel diseases and colorectal cancer and the evolving concept of mitochondrial impairment as a consequence versus initiator of the disease.

Key points

  • Mitochondrial health is vital for epithelial barrier function, comprising paracellular junctions, secreted extracellular barrier (mucus and antimicrobial peptides) and the commensal microbiota that is instrumental in inducing immune tolerance.

  • As signalling organelles, the mitochondria produce factors (mitochondrial reactive oxygen species and released mitochondrial DNA) that perpetuate tissue damage and pathological responses.

  • Mutations in genes involved in mitochondrial function and quality control are associated with inflammatory bowel diseases; inflammatory insults drive mitochondrial dysfunction in inflammatory bowel diseases.

  • Mitochondrial dysfunction in intestinal epithelial cells inhibits oxidative phosphorylation, raising oxygen levels, disrupting mucosal oxygen gradient and causing loss of anaerobes that fuel host epithelium.

  • Mitochondrial dysfunction is associated with alterations to cell types proposed to initiate colorectal cancer tumorigenesis in the presence of chronic insult; in established colorectal cancer, mitochondrial metabolism fuels cancer growth.

  • Mitochondrial-targeted therapeutics could provide a dual approach with current treatments in particular subtypes of patients based on genetic mutations, metabolism or biomarkers of mitochondrial stress.

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Fig. 1: Canonical metabolic pathways in a cell.
Fig. 2: Mitochondrial dysfunction in inflammatory bowel diseases.
Fig. 3: Mitochondria in different stages of colorectal cancer.
Fig. 4: Inflammatory bowel diseases and colorectal cancer therapeutics involving mitochondria.

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Acknowledgements

This work was supported by the National Institutes of Health R01-DK117001 (A.L.T.), National Institutes of Health R01-DK095662 (T.A.B.), Crohn’s Colitis Foundation SRA 900820 (A.L.T.), Crohn’s and Colitis Foundation, Litwin Award 993820 (T.A.B.), Veteran’s Affairs BLRD MERIT IBX005288 (A.L.T.), Veteran’s Affairs CSRD MERIT 1I01CX001353 (T.A.B.) and GI & Liver Innate Immune Program (GALIIP) — University of Colorado Anschutz (A.L.T.).

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA

    Parsa S. Haque & Arianne L. Theiss

  2. Department of Medicine, Division of Digestive Diseases and Nutrition, University of Kentucky College of Medicine, Lexington, KY, USA

    Neeraj Kapur & Terrence A. Barrett

  3. Lexington Veterans Affairs Medical Center Kentucky, Lexington, KY, USA

    Terrence A. Barrett

  4. Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA

    Arianne L. Theiss

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All authors researched data for the article. A.L.T. and T.A.B. contributed substantially to discussion of the content. All authors wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Haque, P.S., Kapur, N., Barrett, T.A. et al. Mitochondrial function and gastrointestinal diseases. Nat Rev Gastroenterol Hepatol (2024). https://doi.org/10.1038/s41575-024-00931-2

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