Mitochondrial miRNA profiling in db/db mice heart

Background: Excessive reactive oxygen species (ROS) generated in the mitochondria is known to be a causal event in diabetic cardiomyopathy. Multiple recent studies suggest that nuclear genome-encoded miRNAs are able to translocate to the mitochondria to modulate mitochondrial activities(1,2), but the medical significance of such new miRNA function has remained unclear. Methods and Results: We observed a marked reduction of the 13 mitochondrial genes in the heart of db/db mice compared with C57 controls. Down-regulation of mitochondrial genes by siRNA recaptured some key disease features, including elevated ROS production. Microarray revealed that 34 miRNAs were upregulated and 90 miRNAs were downregulated in mitochondria of db/db heart. Through computational prediction, we found that each downregulated miRNA targeted an average of 4.9 mitochondrial genes, while each upregulated miRNA targeted an average of 2.9 mitochondrial genes. Re-expression of downregulated miRNAs into H9c2 cells led to enhanced mitochondrial genes translation and reduced ROS production. Conclusions: Our findings suggest that reduced mitochondrial miRNAs in db/db heart contribute to impaired mitochondrial genes expression and elevated ROS production. Re-expression of downregulated miRNAs enhances mitochondrial translation, which is sufficient to reduce ROS production. This observation suggests a novel theoretical ground for developing miRNA-based therapeutics against diabetic cardiomyopathy.