Regulating microRNA expression: at the heart of diabetes mellitus and the mitochondrion

Type 2 diabetes mellitus is a major risk factor for cardiovascular disease and mortality. Uncontrolled type 2 diabetes mellitus results in a systemic milieu of increased circulating glucose and fatty acids. The development of insulin resistance in cardiac tissue decreases cellular glucose import and enhances mitochondrial fatty acid uptake. While triacylglycerol and cytotoxic lipid species begin to accumulate in the cardiomyocyte, the energy substrate utilization ratio of free fatty acids to glucose changes to almost entirely free fatty acids. Accumulating evidence suggests a role of miRNA in mediating this metabolic transition. Energy substrate metabolism, apoptosis, and the production and response to excess reactive oxygen species are regulated by miRNA expression. The current momentum for understanding the dynamics of miRNA expression is limited by a lack of understanding of how miRNA expression is controlled. While miRNAs are important regulators in both normal and pathological states, an additional layer of complexity is added when regulation of miRNA regulators is considered. miRNA expression is known to be regulated through a number of mechanisms, which include, but are not limited to, epigenetics, exosomal transport, processing, and posttranscriptional sequestration. The purpose of this review is to outline how mitochondrial processes are regulated by miRNAs in the diabetic heart. Furthermore, we will highlight the regulatory mechanisms, such as epigenetics, exosomal transport, miRNA processing, and posttranslational sequestration, that participate as regulators of miRNA expression. Additionally, current and future treatment strategies targeting dysfunctional mitochondrial processes in the diseased myocardium, as well as emerging miRNA-based therapies, will be summarized.