2. Academic Validation
  3. Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease

Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease

  • Sci Transl Med. 2025 Jan 15;17(781):eadn8699. doi: 10.1126/scitranslmed.adn8699.
Li-Li Bao 1,  Yu-Qiang Yu 1,  Miguel González-Acera 1,  Jay V Patankar 1,  Andreas Giessl 2,  Gregor Sturm 3,  Anja A Kühl 4 5,  Raja Atreya 1 6,  Lena Erkert 1,  Reyes Gámez-Belmonte 1,  Susanne M Krug 4,  Benjamin Schmid 7,  Philipp Tripal 7,  Mircea T Chiriac 1,  Kai Hildner 1 6,  Britta Siegmund 4,  Stefan Wirtz 1,  Michael Stürzl 8,  Mariam Mohamed Abdou 8,  Zlatko Trajanoski 3,  TRR241 IBDome Consortium,  Markus F Neurath 1 6,  Antonio Zorzano 9 10 11,  Christoph Becker 1 6
Affiliations

Affiliations

  • 1 Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91052 Erlangen, Germany.
  • 2 Department of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany.
  • 3 Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
  • 4 Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany.
  • 5 iPATH.Berlin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, 10117 Berlin, Germany.
  • 6 Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany.
  • 7 Optical Imaging Centre Erlangen (OICE), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91058 Erlangen, Germany.
  • 8 Division of Molecular and Experimental Surgery, Department of Surgery, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany.
  • 9 Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.
  • 10 Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain.
  • 11 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain.
PMID: 39813315 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.

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