Global miRNA expression reveals novel nuclear and mitochondrial interactions in Type 1 diabetes mellitus

Abstract

Background: Considering the potential role of miRNAs as biomarkers and their interaction with both nuclear and mitochondrial genes, we investigated the miRNA expression profile in type 1 diabetes (T1DM) patients, including the pathways in which they are involved considering both nuclear and mitochondrial functions.

Methods: We analyzed samples of T1DM patients and control individuals (normal glucose tolerance) by high throughput miRNA sequencing (miRNome). Next, five miRNAs - hsa-miR-26b-5p, hsa-let-7i-5p, hsa-miR-143-3p, hsa-miR-501-3p and hsa-miR-100-5p - were validated by RT-qPCR. The identification of target genes was extracted from miRTarBase and mitoXplorer database. We also performed receiver operating characteristic (ROC) curves and miRNAs that had an AUC > 0.85 were considered potential biomarkers.

Results: Overall, 41 miRNAs were differentially expressed in T1DM patients compared to control. Hsa-miR-21-5p had the highest number of predicted target genes and was associated with several pathways, including insulin signaling and apoptosis. 34.1% (14/41) of the differentially expressed miRNAs also targeted mitochondrial genes, and 80.5% (33/41) of them targeted nuclear genes involved in the mitochondrial metabolism. All five validated miRNAs were upregulated in T1DM. Among them, hsa-miR-26b-5p showed AUC>0.85, being suggested as potential biomarker to T1DM.

Conclusion: Our results demonstrated 41 DE miRNAs that had a great accuracy in discriminating T1DM and control group. Furthermore, we demonstrate the influence of these miRNAs on numerous metabolic pathways, including mitochondrial metabolism. Hsa-miR-26b-5p and hsa-miR-21-5p were highlighted in our results, possibly acting on nuclear and mitochondrial dysfunction and, subsequently, T1DM dysregulation.

Keywords: miRNAs; miRnome; mitochondrial target; nuclear target; type 1 diabetes.