{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T14:30:40Z","timestamp":1761921040387,"version":"3.41.2"},"reference-count":33,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T00:00:00Z","timestamp":1661731200000},"content-version":"vor","delay-in-days":240,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wuhan clinical medical research project","award":["WX15C20"],"award-info":[{"award-number":["WX15C20"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["BioMed Research International"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p><jats:italic>Objective<\/jats:italic>. Pendrin is encoded by SLC26A4, which is expressed in the apical membrane of inner ear epithelial cells and drives chloride reabsorption in the apical septum. In the inner ear, pendrin dysfunction and hypofunctional mutations lead to vestibular aqueduct (EVA) enlargement and sensory neural hearing loss. Mutations in SLC26A4 are a common reason of deafness. However, the underlying mechanisms of SLC26A4 mutants in hearing loss remain unknown. <jats:italic>Methods<\/jats:italic>. In the present study, pEGFP\u2010N1 carrying wild\u2010type and mutant SLC26A4 (c.85G&gt;A, c.2006A&gt;T, and c.853G&gt;A) were transfected into HEK\u2010293T cells. GFP fluorescence and GFP levels were determined. SLC26A4 mRNA levels were examined by quantitative real\u2010time polymerase chain reaction (qRT\u2010PCR). Then, the expression of chloride intracellular channel 1 (CLIC1) and CLIC2 was measured by Immunofluorescence assay. Intracellular chloride concentration and apoptotic rate were analyzed by flow cytometry. The levels of membrane\/cytoplasmic pendrin, apoptosis\u2010associated proteins, and the PI3K\/Akt\/mTOR pathway members were determined by Western blot. <jats:italic>Results<\/jats:italic>. Constructed SLC26A4 mutant 1 (c.85G&gt;A), SLC26A4 mutant 2 (c.2006A&gt;T), and SLC26A4 mutant 3 (c.853G&gt;A). The wild\u2010type and 3 mutations were stably expressed in HEK\u2010293T. SLC26A4 mRNA expression was significantly increased after transfection with wild\u2010type SLC26A4 and mutant SLC26A4 compared with the untransfected vector group (<jats:italic>P<\/jats:italic> &lt; 0.01). Compared with the vector group, the expression levels of membrane pendrin, cytoplasmic pendrin, CLIC1, CLIC2, Bcl\u20102, p\u2010PI3K, p\u2010Akt, and p\u2010mTOR were upregulated. Compared with the vector group, the chloride concentration, cell apoptotic rate, and the expression levels of caspase\u20103, caspase\u20109, and Bax were downregulated. Compared with the vector group, the above effects of SLC26A4 were reversed after the SLC26A4 mutant. <jats:italic>Conclusion<\/jats:italic>. After SLC26A4 mutation, pendrin was transferred from the membrane, the chloride intracellular channel function was reduced, and the excessive accumulation of chloride in the cytoplasm induced cell apoptosis by inhibited PI3K\/Akt\/mTOR pathway phosphorylation.<\/jats:p>","DOI":"10.1155\/2022\/6496799","type":"journal-article","created":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T03:35:20Z","timestamp":1661830520000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["SLC26A4 Mutation Promotes Cell Apoptosis by Inducing Pendrin Transfer, Reducing Cl<sup>-<\/sup> Transport, and Inhibiting PI3K\/Akt\/mTOR 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