Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease

Bao L, Yu Y, Gonzalez Acera M, Patankar J, Gießl A, Sturm G, Kühl AA, Atreya R, Erkert L, Gamez-Belmonte R, Krug SM, Schmid B, Tripal P, Chiriac MT, Hildner K, Siegmund B, Wirtz S, Stürzl M, Mohamed Abdou M, Trajanoski Z, Neurath M, Zorzano A, Becker C (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Science Translational Medicine American Association for the Advancement of Science

Book Volume: 17

Article Number: eadn8699

Journal Issue: 781

DOI: 10.1126/scitranslmed.adn8699

Abstract

Dysregulation at the intestinal epithelial barrier is a driver of inflammatory bowel disease (IBD). However, the molecular mechanisms of barrier failure are not well understood. Here, we demonstrate dysregulated mitochondrial fusion in intestinal epithelial cells (IECs) of patients with IBD and show that impaired fusion is sufficient to drive chronic intestinal inflammation. We found reduced expression of mitochondrial fusion–related genes, such as the dynamin-related guanosine triphosphatase (GTPase) optic atrophy 1 (OPA1), and fragmented mitochondrial networks in crypt IECs of patients with IBD. Mice with Opa1 deficiency in the gut epithelium (Opa1i∆IEC) spontaneously developed chronic intestinal inflammation with mucosal ulcerations and immune cell infiltration. Intestinal inflammation in Opa1i∆IEC mice was driven by microbial translocation and associated with epithelial progenitor cell death and gut barrier dysfunction. Opa1-deficient epithelial cells and human organoids exposed to a pharmacological OPA1 inhibitor showed disruption of the mitochondrial network with mitochondrial fragmentation and changes in mitochondrial size, ultrastructure, and function, resembling changes observed in patient samples. Pharmacological inhibition of the GTPase dynamin-1–like protein in organoids derived from Opa1i∆IEC mice partially reverted this phenotype. Together, our data demonstrate a role for epithelial OPA1 in regulating intestinal immune homeostasis and epithelial barrier function. Our data provide a mechanistic explanation for the observed mitochondrial dysfunction in IBD and identify mitochondrial fusion as a potential therapeutic target in this disease.

Authors with CRIS profile

Lili Bao Professur für Molekulare Gastroenterologie Yidong Yu Professur für Klinische Mikrobiologie und Immunologie Miguel Gonzalez Acera Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Jay Patankar Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Andreas Gießl Department of Ophthalmology Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen Lena Erkert Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Maria de los Reyes Gámez Belmonte Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Benjamin Schmid Optical Imaging Center Erlangen (OICE) Philipp Tripal Optical Imaging Center Erlangen (OICE) Mircea-Teodor Chiriac Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Kai Hildner Professur für Mukosale Immuntherapie Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Michael Stürzl Professur für Molekulare und Experimentelle Chirurgie Mariam Mohamed Abdou Professur für Molekulare und Experimentelle Chirurgie Markus Neurath Lehrstuhl für Innere Medizin I (Medizin 1) Christoph Becker Professur für Molekulare Gastroenterologie

Involved external institutions

Charité - Universitätsmedizin Berlin DE Germany (DE) Institute for Research in Biomedicine / IRB Barcelona ES Spain (ES) Medizinische Universität Innsbruck AT Austria (AT)

How to cite

APA:

Bao, L., Yu, Y., Gonzalez Acera, M., Patankar, J., Gießl, A., Sturm, G.,... Becker, C. (2025). Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease. Science Translational Medicine, 17(781). https://doi.org/10.1126/scitranslmed.adn8699

MLA:

Bao, Lili, et al. "Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease." Science Translational Medicine 17.781 (2025).

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