Krishnan, PreethiBranco, Renato Chaves SoutoWeaver, Staci A.Chang, GarrickLee, Chih-ChunSyed, FarooqEvans-Molina, Carmella2024-12-132024-12-132024Krishnan P, Branco RCS, Weaver SA, et al. miR-146a-5p mediates inflammation-induced β cell mitochondrial dysfunction and apoptosis. J Biol Chem. 2024;300(11):107827. doi:10.1016/j.jbc.2024.107827https://hdl.handle.net/1805/45007We previously showed that miR-146a-5p is upregulated in pancreatic islets treated with proinflammatory cytokines. Others have reported that miR-146a-5p overexpression is associated with β cell apoptosis and impaired insulin secretion. However, the molecular mechanisms mediating these effects remain elusive. To investigate the role of miR-146a-5p in β cell function, we developed stable MIN6 cell lines to either overexpress or inhibit the expression of miR-146a-5p. Monoclonal cell populations were treated with proinflammatory cytokines (interleukin-1β, interferonγ, and tumor necrosis factor α) to model type 1 diabetes in vitro. We found that overexpression of miR-146a-5p increased cell death under conditions of inflammatory stress and led to mitochondrial membrane depolarization, whereas inhibition of miR-146a-5p reversed these effects. Additionally, inhibition of miR-146a-5p increased insulin secretion, mitochondrial DNA copy number, respiration rate, and ATP production. Further, RNA-seq data showed enrichment of pathways related to insulin secretion, apoptosis, and mitochondrial function when the expression levels of miR-146a-5p were altered. Finally, a temporal increase in miR-146a-5p expression levels and a decrease in mitochondria function markers were observed in islets derived from nonobese diabetic mice. Collectively, these data suggest that miR-146a-5p may promote β cell dysfunction and death during inflammatory stress by suppressing mitochondrial function.en-USAttribution 4.0 InternationalMIN6 cellsDiabetesInsulinmiR-146a-5pMicroRNAMitochondrial functionPancreatic isletsβ cellArticle