Mitochondria Associated MicroRNA Expression Profiling of Heart Failure

Abstract

Heart failure (HF) is associated with mitochondrial dysfunction and energy metabolism impairment. MicroRNAs are implicated in the development of heart failure. However, the mitochondria enriched microRNA during heart failure remains elusive. Here, we generated a pressure overload-induced early and late stage heart failure model at 4 weeks and 8 weeks following transverse aortic constriction (TAC) in mice. We found that expression of mitochondrion protein COX4 was highly enriched in isolated mitochondria from cardiac tissues while GAPDH could hardly be detected. Furthermore, small RNA sequencing for mitochondria RNAs from failing hearts was performed. It was found that 69 microRNAs were upregulated and 2 were downregulated in early heart failure, while 16 microRNAs were upregulated and 6 were downregulated in late heart failure. 15 microRNA candidates were measured in both mitochondria and total cardiac tissues of heart failure by real-time PCR. MiR-696, miR-532, miR-690, and miR-345-3p were enriched in mitochondria from the failing heart at early stage. Bioinformatics analysis showed that mitochondria enriched microRNAs in HF were associated with energy metabolism and oxidative stress pathway. For the first time, we demonstrated microRNAs were enriched in mitochondria during heart failure, which established a link between microRNA and mitochondrion in heart failure.

Mitochondrial MiRNA in Cardiovascular Function and Disease

“…In addition, some of them may target nuclear-encoded mRNAs localized on the mitochondrial surface ( Figure 1). Of importance, differentially expressed mitomiRs were observed in heart failure [33,34]. These findings implicate the important roles of mitomiRs in regulating mitochondrial gene expression and mitochondrial functions in both physiological and pathological conditions.…”

“…In addition, miR-1, miR-210, and miR-338 have been reported to enhance mitochondrial translation, regulate the mitochondrial proteome, and mitochondrial bioenergetics in myocytes [40,[44][45][46]. Bioinformatics analysis showed that mitochondria enriched miR-696, miR-532, miR-690, and miR-345-3p at the early stage of the failing heart, and these miRNAs were associated with energy metabolism and oxidative stress pathways [33]. More recently, in hypoxic/reoxygenated cardiomyocytes, miR-762, miR-744, miR-92a, miR-1892, miR-150, miR-669a, miR-296-3p, miR-711, and miR-450a-3p were found to translocate into the mitochondria, whereas miR-362-5p, miR-532-5p, miR-31, miR-139-5p, miR-330, and miR-379 were decreased in the mitochondria [47].…”

“…Mitochondrial metabolism and dynamics are essential for the biological processes in physiological conditions, and alterations in either dynamics or metabolism could lead to cardiovascular disease initiation and progression [56,57]. MitomiRs regulate mitochondrial energy status, glycolysis, and the expression of genes necessary for mitochondrial metabolism to contribute to cardiovascular health and pathogenesis [33]. For example, mitomiR miR-181c played a role in electron chain complex IV remodeling in cardiomyocytes, with the levels enriched two-fold in the mitochondria compared to the whole heart [31,58,59].…”

“…The lack of balance between ATP demand and production is a defining feature in HF development. Various mitomiRs contribute to the altered energy metabolism, oxidative stress, cell survival, and apoptosis in HF [17,33,40]. Changes in these miRNAs influence the occurrence and progression of HF.…”

MicroRNA files in the prevention of intestinal ischemia/reperfusion injury by hydrogen rich saline

“…Regarding miR-199a-3p, the most drastically altered miRNA in the miRNomes in HRS-pretreated intestinal I/R injury, has never been reported in intestinal diseases. Interestingly, miR-199a-3p, miR-5126, and miR-6538 have been listed together among the top differentially expressed miRNAs in mitochondria from the failing heart at late stage, suggesting link to energy metabolism, oxidative stress, and apoptosis [30]. Specifically, study has highlighted that miR-199a-3p inhibits cell proliferation and induces apoptosis in human hepatocellular carcinoma [31].…”