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- W4366451343 abstract "Abstract Intestinal barrier defect is a hallmark of inflammatory bowel disease (IBD). Mitochondrial dysfunction results in energy deficiency and oxidative stress, which contribute to the pathogenesis of IBD. Arrestin beta 1 (ARRB1) is a negative regulator that promotes G protein-coupled receptors (GPCRs)desensitization, endocytosis, and degradation. Our previous study indicated that ARRB1 was involved in mucosal protection in colitis; however, its role in maintaining the intestinal barrier is still unclear. In the present study, we demonstrated that ARRB1 protected the intestinal tight junction barrier against experimental colitis in vivo . ARRB1 deficiency was accompanied by abnormal mitochondrial morphology, lower ATP production, and severe oxidative stress. In vitro , the knockdown of ARRB1 reduced ATP levels and mitochondrial membrane potential while increasing reactive oxygen species levels and oxidative stress. Upon ARRB1 ablation, mitophagy was inhibited, accompanied by decreased LC3BII, phosphatase and tension homologue induced protein kinase1 (PINK1) and parkin, but increased p62 expression. Mitophagy inhibition via PINK1 siRNA or mitochondrial division inhibitor 1 (Mdivi-1) impaired ARRB1-mediated tight junction protection. Mitofusin2 is a critical ubiquitinated substrate for parkin accumulation in mitochondria. Co-immunoprecipitation and luciferase assays indicated that the interaction of ARRB1 with E2F1 activated mitophagy by enhancing the transcription of mitofusin2. Thus, our results suggest that ARRB1 is critical to maintaining the intestinal tight junction barrier by modulating mitophagy. This finding indicates that ARRB1 might be a potential therapeutic target to prevent IBD progression by maintaining mitochondrial homeostasis." @default.
- W4366451343 created "2023-04-22" @default.
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- W4366451343 date "2023-04-19" @default.
- W4366451343 modified "2023-10-06" @default.
- W4366451343 title "ARRB1 Protects Intestinal Tight Junction through Promoting Mitofusin 2 Transcription to Drive Parkin-dependent Mitophagy in Colitis" @default.
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- W4366451343 doi "https://doi.org/10.21203/rs.3.rs-2726544/v1" @default.
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