MiR-208 inhibits mitochondrial cardiomyocyte respiration in diabetic patients by inhibiting cytochrome C oxidase expression

Abstract

Diabetes is a common disease that is characterized by myocardial mitochondrial dysfunction. MicroRNAs are small non-coding RNAs that participate in the post-transcriptional regulation of many signaling pathways, and are involved in diabetes and mitochondrial function. The aim of this study was to investigate whether cardiac mitochondrial dysfunction observed in diabetic patients could be related to alteration in non-coding RNAs as suggested in bench-side studies. A study of the non-coding transcriptome by microarrays was performed on 16 matched pairs of atrial myocardial samples from diabetic and non-diabetic patients who underwent aortic valve replacement and/or coronary artery bypass graft surgery at Lille University Hospital. Mitochondrial respiration in myocardial homogenates and expression of microRNAs identified by the transcriptomic analysis were studied in myocardial samples from a second population. Analysis of the non-coding transcriptome revealed four microRNAs significantly deregulated in diabetic patients and predicted to target mitochondrial oxidative phosphorylation gene transcripts by bioinformatic analysis, i.e. miR-208, miR-4738, miR-498 and miR-1. Interestingly, in line with the predicted interaction between miR-208 and cytochrome C oxidase transcript, a significant negative correlation was observed between this miR expression level and complex IV-dependent mitochondrial respiration and complex activity ( Fig. 1 ). miR-208 is likely linked to decreased cardiac expression of cytochrome c oxidase and subsequent depressed complex IV-dependent mitochondrial respiration in the myocardium of diabetic patients.