Open AccessPKC α replaces AMPK to regulate mitophagy: Another PEDF role on ischaemic cardioprotection
Author(s) -
Miao Haoran,
Qiu Fan,
Huang Bing,
Liu Xiucheng,
Zhang Hao,
Liu Zhiwei,
Yuan Yanliang,
Zhao Qixiang,
Zhang Hu,
Dong Hongyan,
Zhang Zhongming
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13849
Subject(s) - mitophagy , ampk , microbiology and biotechnology , protein kinase c , phosphorylation , pedf , autophagy , chemistry , protein kinase a , kinase , biology , biochemistry , retinal , apoptosis
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 ( PKC α) and phospho‐ PKC α (p‐ PKC α) contents to promote mitophagy. Thus, we investigated the association between PKC α and mitophagy. Here we identify an interaction between PKC α and Unc‐51‐like kinase 1 ( ULK 1), essential component of mitophagy. Further analyses show this is a direct interaction within a domain of ULK 1 that termed the serine/threonine‐rich domain (S/T domain). Notably, a deletion mutant ULK 1 that lacks the binding domain is defective in mediating PEDF ‐induced mitophagy. Furthermore, we demonstrate that ULK 1 is phosphorylated at Ser317/555/777 and Raptor is also phosphorylated by phospho‐ PKC α. Phospho‐ ULK 1 (p‐ ULK 1) 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 ULK 1 and PKC α that can replace the AMPK ‐dependent mitophagy processes.