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

Haoran Miao,Xiucheng Liu,Fan Qiu,Zhongming Zhang,Hao Zhang,Zhiwei Liu,Qixiang Zhao,Yanliang Yuan,Bing Huang,Hu Zhang,Hongyan Dong

doi:10.1111/jcmm.13849

Abstract

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.

Highlights

Acute myocardial infarction (AMI), the primary component of cardiovascular disease, is the leading cause of morbidity and mortality worldwide.[1,2] Owing to the development of therapeutic intervention, morbidity and mortality have decreased markedly in recent decades
We show that the phospho‐Unc‐51‐like kinase 1 (ULK1) induced by pigment epithelium‐derived factor (PEDF)‐protein kinase Cα (PKCα) promotes FUNDC1‐mediated mitophagy and decrease the release of mitochondrial ROS and DNA, indicating that PEDF cardioprotective regulation of mitophagy is associated with PKCα rather than AMPK
PKCα consists of 672 amino acids and is distributed in all tissues, in contrast to other PKC isotypes whose expression is restricted in the particular tissues.[25,26]

Summary

Introduction

Acute myocardial infarction (AMI), the primary component of cardiovascular disease, is the leading cause of morbidity and mortality worldwide.[1,2] Owing to the development of therapeutic intervention, morbidity and mortality have decreased markedly in recent decades. The burden of myocardial infarction and the incidence of heart failure as the end‐stage of left ventricular remodelling remain high.[3]. Mitochondria, the primary organelles of energy production and cell death, maintain their integrity by the intraorganellar proteolytic system and the dynamic nature of the mitochondrial population in ischemic cardiomyocytes.

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