PEDF protects cardiomyocytes by promoting FUNDC1-mediated mitophagy via PEDF-R under hypoxic condition

Pigment epithelial-derived factor (PEDF) is known to exert diverse physiological activities. Previous studies suggest that hypoxia could induce mitophagy. Astoundingly, under hypoxic condition, we found that PEDF decreased the mitochondrial density of cardiomyocytes. In this study, we evaluated whether PEDF could decrease the mitochondrial density and play a protective role in hypoxic cardiomyocytes via promoting mitophagy. Immunostaining and western blotting were used to analyze mitochondrial density and mitophagy of hypoxic cardiomyocytes. Gas chromatography-mass spectrometry and ELISA were used to analyze levels of palmitic acid and diacylglycerol. Transmission Electron Microscopy was used to detect mitophagy and the mitochondrial density in adult male Sprague-Dawley rat model of acute myocardial infarction. Compared to the control group, we observed that PEDF decreased mitochondrial density through promoting hypoxic cardiomyocyte mitophagy. PEDF increased the levels of palmitic acid and diacylglycerol, and then upregulated the levels of protein kinase Cα (PKC-α) and its activation. Furthermore, inhibition of PKC-α by Go6976 could effectively suppress PEDF-induced mitophagy. Besides, we found that PEDF promoted FUNDC1-mediated cardiomyocyte mitophagy via ULK1, which depended on the activation of PKC-α. Finally, we discovered that mitophagy was increased and mitochondrial density was reduced in adult male Sprague-Dawley rat model of acute myocardial infarction. We concluded that PEDF promotes mitophagy to protect hypoxic cardiomyocytes, through PEDF/PEDF-R/PA/DAG/PKC-α/ULK1/FUNDC1 pathway.