MiR-130a Regulates FUNDC1-Mediated Mitophagy by Targeting GJA1 in Myocardial Ischemia/Reperfusion Injury

Abstract

To understand the complex pathogenesis in myocardial ischemia/reperfusion (I/R) injury (IRI) is the urgent problem solved in clinical trials. Increasing evidences have suggested that miRNAs are involved in the occurrence and development of heart diseases by regulating the mitochondria-related genes expression. Mitochondria have been acknowledged as the key triggers of cardiac I/R injury. However, the potential impact of miR-130a on mitochondria remains unclear in myocardial IRI. Exploring the regulatory mechanism of miR-130a on mitochondria may provide a new target for IRI therapy. In the present study, we found that miR-130a was significantly increased in the acute myocardial infarction (AMI) patients and myocardial I/R rats. Over-expression of miR-130a resulted in mitochondrial dysfunction, evidenced by decreases in mitochondrial ATP production rate as well as mitochondrial membrane potential (MMP), and increase in reactive oxygen species (ROS) production. However, suppression of miR-130a could protect mitochondrial damage, showing elevation of mitochondrial ATP production rate and MMP, and reduction of ROS production. We further explored the effect of miR-130a on mitochondrial quality control (MQC) system by determining mitochondrial-protein-specific proteases, and mitochondrial morphology was analyzed by fluorescence imaging and electron microscopy, respectively. It was noted that miR-130a could obviously suppress mitochondrial fusion and FUNDC1-mediated mitophagy to accelerate myocardial IRI. Moreover, we investigated the potential miR-130a targetd mitochondria-related genes to understand the regulatory mechanism of miR-130a in the setting of myocardial IRI. It was revealed that miR-130a evidently targeted GJA1, and GJA1 rescued IRI through protecting MMP and activating mitophagy. In addition, knockdown of miR-130a significantly activated FUNDC1-mediated mitophagy, while knockdown of GJA1 reversed the relevant response. Collectively, our findings suggest that miR-130a regulates FUNDC1-mediated mitophagy by targeting GJA1 in myocardial IRI.