MiR-25 Protects Cardiomyocytes against Oxidative Damage by Targeting the Mitochondrial Calcium Uniporter

Abstract

MicroRNAs (miRNAs) are a class of small non-coding RNAs, whose expression levels vary in different cell types and tissues. Emerging evidence indicates that tissue-specific and -enriched miRNAs are closely associated with cellular development and stress responses in their tissues. MiR-25 has been documented to be abundant in cardiomyocytes, but its function in the heart remains unknown. Here, we report that miR-25 can protect cardiomyocytes against oxidative damage by down-regulating mitochondrial calcium uniporter (MCU). MiR-25 was markedly elevated in response to oxidative stimulation in cardiomyocytes. Further overexpression of miR-25 protected cardiomyocytes against oxidative damage by inactivating the mitochondrial apoptosis pathway. MCU was identified as a potential target of miR-25 by bioinformatical analysis. MCU mRNA level was reversely correlated with miR-25 under the exposure of H2O2, and MCU protein level was largely decreased by miR-25 overexpression. The luciferase reporter assay confirmed that miR-25 bound directly to the 3' untranslated region (UTR) of MCU mRNA. MiR-25 significantly decreased H2O2-induced elevation of mitochondrial Ca2+ concentration, which is likely to be the result of decreased activity of MCU. We conclude that miR-25 targets MCU to protect cardiomyocytes against oxidative damages. This finding provides novel insights into the involvement of miRNAs in oxidative stress in cardiomyocytes.

Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell–Derived Exosomes From Pediatric Patients

“…PLSR analysis gave quantitative outputs to how likely each microRNA was involved in our response. Certain microRNA’s identified by our anaylsis have been shown to regulate important function like fibrosis (miR-27a and miR-29c 26, 27 ), cardiac hypertrophy (miR-29c 28 , miR-96 29, 30 , miR-182 31, 32 and miR-185 33 ), angiogenesis (miR-27a 34 ), and apoptotsis (miR-138 35, 36 , miR-25 37 ). Although, our model is predictive of microRNA-based mechanism, these targets still need to be validated in the future studies.…”

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

“…However, the changes we see here likely reflect a regulatory pathway rather than heart failure epiphenomena, as we found similar magnitudes and concordant changes across all the core uniporter subunits assayed. Potential mechanisms for regulating the uniporter include altering transcript expression[63], changing channel conductance[64, 65], changing channel oligomerization state[66–68], or changing channel sensitivity to cytoplasmic Ca 2+ [51]. Future studies will need to establish the regulatory mechanism active in Tfam KO hearts and whether it stabilizes the channel or modifies its underlying behavior.…”

Effects of miRNAs on myocardial apoptosis by modulating mitochondria related proteins

“…MiR‐145 and miR‐25 can reduce Ca 2+ overload and mitochondrial ROS stress by suppressing expression of calcium/calmodulin dependent protein kinase II (CaMKII) and mitochondrial calcium uniporter (MCU), respectively. Likewise, miR‐214 inhibits sodium/calcium exchanger 1(Ncx1) and thereby it protected cardiac cells from oxidative damage caused by Ca 2+ overload induced ROS generation . Interestingly, miR‐22 showed differential effects in cardiac cells depends on the pathological circumstances such as hypoxia and I/R pressure.…”