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

Abstract

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.

Keywords: diabetes; epigenetics; exosomes; long noncoding RNA; metabolism; miRNA processing.

Fig. 1.

Regulation of miRNA regulators. The expression of miRNAs is controlled through multiple factors. Epigenetic regulation includes hypermethylation of the miRNA-184 CpG loci, pri-miRNA-208b tethering to increase enhancer of zeste homolog 2 binding, and miRNA interactions with DNA methyl transferase (DNMT)1, DNMT3a, and DNMT3b. Regulation of miRNA expression through miRNA processing is dependent on Dicer expression (miRNA-103) and protein-protein interactions with Dicer (miRNA-21). Other proteins, such as GTPase-activating protein-binding protein 1, can affect processing (miRNA-1). Long noncoding RNA (lncRNA) can regulate miRNA expression by acting as a “sponge,” sequestering native and exogenous miRNAs, such as miRNA-188-3p, miRNA-539, and miRNA-489. Also, exosomal release/transport of miRNA-1, miRNA-21, and miRNA-133a can alter miRNA expression.

Fig. 2.

miRNA influence on signaling pathways in the diabetic heart. miRNA regulation of cardiomyocyte energy metabolism (blue), survival (green), and apoptosis (red) in the diabetic heart is shown. The up or down arrows beside each miRNA species indicate its upregulation or downregulation in the diabetic heart, respectively (Table 1). The marked line connecting each miRNA with its target demonstrates that the miRNA inhibits its target. Subcellular components have been labeled as follows: plasma membrane (yellow), cytoplasm (green), and mitochondrion (blue). CAV2, caveolin 2; IR, insulin receptor; IRS2, insulin receptor substrate 2; PI3K, phosphatidylinositol 4,5-bisphosphate 3-kinase; GLUT4, glucose transporter type 4; FA, fatty acid; TR4, testicular receptor 4; FAO, fatty acid oxidation; PPARa, peroxisome proliferator-activated receptor-α; PGC1a, peroxisome proliferator-activated receptor-γ coactivator-1α; ISCU1/2, iron-sulfur cluster assembly proteins; C1−C4, electron transport chain complexes 1–4; F₀, ATP synthase subunit F₀; F₁, ATP synthase subunit F₁; Slc25a3, mitochondrial phosphate carrier protein; CytC, cytochrome c; Sirt1, sirtuin 1.

Fig. 3.

Predicted interactions of miRNA with DNA methyltransferase (DNMT)1. Ingenuity Pathway Analysis provides potential areas for future epigenetic/miRNA analyses. The predicted connections include mature miRNAs and miRNA seed sequences, which have been suggested to interact with DNMT1, DNMT3a, or DNMT3b. miRNAs with listed seed sequences can account for one or many miRNAs that contain similar regions suggested to promote protein/miRNA or mRNA/miRNA interactions with DNMTs.