Intestinal immune homeostasis relies on intestinal epithelial cells (IECs) to provide a dynamic gut barrier, but also to negotiate tolerance between the microbiome in the gut lumen and the mucosal immune system in the bowel wall. While dysregulation of the epithelial barrier has been implicated as a key driver of inflammatory bowel disease (IBD), the molecular mechanisms underlying such dysregulation are not well understood. Here, we demonstrate a critical role for epithelial Optic atrophy 1 (OPA1), a dynamin-related guanosine triphosphatase (GTPase) involved in mitochondrial fusion, in intestinal barrier integrity and gut immune homeostasis. Mitochondrial fusion-related genes, including OPA1, were negatively regulated in experimental intestinal inflammation and in patients with IBD. Importantly, we found fragmented mitochondrial networks in intestinal crypts of IBD patients, suggesting a role for mitochondrial fission and fusion in the pathogenesis of these diseases. Mice with a conditional knockout of Opa1 in IECs (Opa1i∆IEC) spontaneously developed chronic intestinal inflammation, characterized by mucosal ulceration and immune cell infiltration. This inflammation in Opa1i∆IEC mice was driven by microbial translocation and was associated with increased cell death in IECs and impaired barrier function. Opa1-deficient IECs, as well as human organoids with OPA1 inhibition, exhibited disruption of the mitochondrial network, including mitochondrial fragmentation, altered size and ultrastructure, closely resembling those seen in IBD patient samples. Pharmacological inhibition of the GTPase dynamin-1-like (Drp1) protein partially reversed this phenotype. In summary, our findings highlight the essential role of epithelial OPA1 in maintaining intestinal immune homeostasis and epithelial barrier function. These results further provide a mechanistic explanation for the mitochondrial dysfunction observed in IBD, and identify mitochondrial fusion as a novel pathway and a potential therapeutic target.
Lili Bao (Thu,) studied this question.