PKCα replaces AMPK to regulate mitophagy: Another PEDF role on ischaemic cardioprotection

Both decreased autophagy positive regulator AMP activated protein kinase (AMPK) level and promoted mitophagy are observed in oxygen‐glucose deprivation (OGD) cardiomyocytes treated with pigment epithelium‐derived factor (PEDF). This contradictory phenomenon and its underlying mechanisms have not been thoroughly elucidated. Our previous study reveals that PEDF increases the protein kinase Cα (PKCα) and phospho‐PKCα (p‐PKCα) contents to promote mitophagy. Thus, we investigated the association between PKCα and mitophagy. Here we identify an interaction between PKCα and Unc‐51‐like kinase 1 (ULK1), essential component of mitophagy. Further analyses show this is a direct interaction within a domain of ULK1 that termed the serine/threonine‐rich domain (S/T domain). Notably, a deletion mutant ULK1 that lacks the binding domain is defective in mediating PEDF‐induced mitophagy. Furthermore, we demonstrate that ULK1 is phosphorylated at Ser317/555/777 and Raptor is also phosphorylated by phospho‐PKCα. Phospho‐ULK1 (p‐ULK1) at these sites are all essential for PEDF‐induced mitophagy and reduce the release of mitochondrial ROS and DNA. This study therefore identifies a previously uncharacterized interaction between the ULK1 and PKCα that can replace the AMPK‐dependent mitophagy processes.