MiR-130a-3p regulates FUNDC1-mediated mitophagy by targeting GJA1 in myocardial ischemia/reperfusion injury

Abstract

Understanding the complex pathogenesis in myocardial ischemia/reperfusion (I/R) injury (IRI) is an urgent problem in clinical trials. Increasing pieces of evidence have suggested that miRNAs are involved in the occurrence and development of heart diseases by regulating mitochondria-related gene 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 significantly increased in acute myocardial infarction (AMI) patients and myocardial I/R rats. MiR-130a could downregulate the viability of cardiomyocytes and the knockdown of miR-130a could protect the viability of cardiomyocytes under hypoxia-reoxygenation (HR). Over-expression of miR-130a resulted in mitochondrial dysfunction. It was evidenced by decreases in mitochondrial ATP production, mitochondrial membrane potential (MMP), and an increase in reactive oxygen species (ROS) production. However, suppression of miR-130a could protect against mitochondrial damage, show elevation of mitochondrial ATP production rate and MMP, and reduce ROS production. We further explored the effect of miR-130a on the mitochondrial quality control (QMC) system by determining mitochondrial-protein-specific proteases and analyzed mitochondrial morphology by fluorescence imaging and electron microscopy, respectively. It was noted that miR-130a could suppress mitochondrial fusion and FUNDC1-mediated mitophagy to accelerate myocardial IRI. Moreover, we investigated the potential miR-130a targeted mitochondria-related genes to understand the regulatory mechanism of miR-130a in the setting of myocardial IRI. It was revealed that miR-130a targeted GJA1, and GJA1 rescued IRI by enhancing ATP production rate and oxidative phosphorylation, meanwhile protecting cell viability, MMP, and activating mitophagy. In addition, the knockdown of miR-130a significantly activated FUNDC1-mediated mitophagy, while the knockdown of GJA1 reversed the relevant response. Collectively, our findings suggest that miR-130a regulates FUNDC1-mediated mitophagy by targeting GJA1 in myocardial IRI.

miRNA‐103‐3p‐Hlf regulates apoptosis and autophagy by targeting hepatic leukaemia factor in heart failure

“…Various miRNAs, such as remodelling, hypertrophy, apoptosis, and hypoxia, play a role in the pathogenic mechanism leading to HF 24 . For example, miR‐130a‐3p regulates FUNDC1‐mediated mitophagy by targeting GJA1 in myocardial ischaemia/reperfusion injury 25 . In addition, miRNAs respond to the progression of HF in a dynamic and stage‐specific manner.…”

Shuangshen Ningxin Capsule alleviates myocardial ischemia-reperfusion injury in miniature pigs by modulating mitophagy:network pharmacology and experiments in vivo

“…These proteins include FUNDC1, BNIP3, and NIX. FUNDC1 is an important receptor protein located in the outer mitochondrial membrane, and when mitochondria are damaged, the LIR motif in FUNDC1 activates mitophagy by molecularly docking with LC3 protein through hydrophobic interaction [19]. BNIP3 is located in the outer mitochondrial membrane and contains a transmembrane domain with the C-terminus inserted into the outer mitochondrial membrane and the N-terminal storm in the cytoplasm.…”

Lipid droplets, autophagy, and ER stress as key (survival) pathways during ischemia‐reperfusion of transplanted grafts

“…IRI causes organ damage and delays return of graft function after transplantation (Yang & Klionsky, 2010). Counteracting cell death by removing damaged macromolecules or organelles makes autophagy an essential focus of IR treatment and prevention strategies during transplantation (Mao et al, 2023). Studies have indicated that autophagy and its regulation are potential therapeutic targets in IRI and offer hope for reducing IRI by enhancing the protective mechanism.…”

“…Although autophagy can promote cell survival by recycling components, excessive autophagy can lead to cell death. Because of this dual pathway, modulation of autophagy may be the key to treating IRI (Mao et al, 2023). Lipid droplets (LDs) are neutral lipid storage organelles that play a crucial role in lipid homeostasis.…”