Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease

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Item Type:	Article
Title:	Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease
Creators Name:	Bao, L.L., Yu, Y.Q., González-Acera, M., Patankar, J.V., Giessl, A., Sturm, G., Kühl, A.A., Atreya, R., Erkert, L., Gámez-Belmonte, R., Krug, S.M., Schmid, B., Tripal, P., Chiriac, M.T., Hildner, K., Siegmund, B., Wirtz, S., Stürzl, M., Mohamed Abdou, M., Trajanoski, Z., Neurath, M.F., Zorzano, A. and Becker, C.
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 (Opa1(i∆IEC)) spontaneously developed chronic intestinal inflammation with mucosal ulcerations and immune cell infiltration. Intestinal inflammation in Opa1(i∆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 Opa1(i∆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.
Keywords:	Epithelial Cells, GTP Phosphohydrolases, Inbred C57BL Mice, Inflammation, Inflammatory Bowel Diseases, Intestinal Mucosa, Mitochondria, Mitochondrial Dynamics, Organoids, Animals, Mice
Source:	Science Translational Medicine
ISSN:	1946-6234
Publisher:	American Association for the Advancement of Science
Volume:	17
Number:	781
Page Range:	eadn8699
Date:	January 2025
Additional Information:	Leif S.H. Ludwig and Ashley Sanders are members of the TRR241 IBDome Consortium.
Official Publication:	https://doi.org/10.1126/scitranslmed.adn8699
PubMed:	View item in PubMed

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