MicroRNA-146a as a Regulator of Cardiac Energy Metabolism.

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Article, see p 747 The heart has a high mitochondrial content to generate the vast amount of ATP that is needed to provide the energy that is required for the continuous mechanical workload. Cellular ATP is predominantly used to support the contraction-relaxation cycle within the myocardium. Although cardiac mitochondria are flexible in using substrates to generate energy, the conversion of free fatty acids and glucose accounts for most of the ATP production in the healthy adult heart.1 However, during advanced stages of heart failure there is an imbalance between energy demand and availability, accompanied by a downregulation of fatty acid oxidation and an increase in glycolysis.2 Glucose becomes an important preferential substrate in the failing heart, and it is suggested that the derangement of the cardiac energy substrate metabolism plays a key role in the pathogenesis of heart failure.3 Manipulations that improve the oxidative capacity of the heart during disease might be beneficial for cardiac function and slow the progression of heart failure. MicroRNAs (miRNAs) are small, noncoding pieces of RNA that regulate gene expression by binding to recognition sequences that are usually located within the 3′-untranslated region (3′-UTR) of target genes. Binding of the miRNA to these sequences blocks the translational activity of these transcripts, leading to a reduction in protein formation.4 As is true for many aspects of heart disease, miRNAs have previously also been shown to be involved in the regulation of energy metabolism during heart failure.5 A miRNA that has been linked to mitochondrial dysfunction of the heart is miR-181c. MiR-181c has been proposed to function in the mitochondrial compartment of cardiomyocytes by targeting mt-COX1 mRNA. Overexpression of miR-181c induced a loss of mt-COX1 expression, which led to an increase in mt-COX2 levels and subsequent remodeling of mitochondrial respiratory complex IV. …