Mitochondrial phosphatase PGAM5 regulates Keap1-mediated Bcl-xL degradation and controls cardiomyocyte apoptosis driven by myocardial ischemia/reperfusion injury.
Phosphoglycerate mutase 5 (PGAM5) is a mitochondrial membrane protein that plays crucial roles in necroptosis and apoptosis. Though PGAM5 is known to be required for inducing intrinsic apoptosis through interacting with BCL2 associated X protein (Bax) and dynamin-related protein 1 (Drp1), the expression and role of PGAM5 in cardiomyocyte apoptosis driven by myocardial ischemia/reperfusion injury(MIRI) has not been studied. The present study shows that PGAM5 expression decreased after MIRI in vivo, positively correlated with Bcl-xL expression, negatively correlated with Kelch-ECH associating protein 1 (Keap1) expression. Furthermore, PGAM5 expression also decreased in cardiomyocytes after hypoxia/reoxygenation (H/R) treatment in vitro. PGAM5 silence promoted cardiomyocyte apoptosis and inhibited Bcl-xL expression, but with no effect on Keap1 expression. Accordingly, Keap1 overexpression further inhibited Bcl-xL and PGAM5 expression. Additionally, PGAM5-Bcl-xL-Keap1 interaction was identified, suggesting that PGAM5 might participate in the degradation of Bcl-xL mediated by Keap1. In summary, PGAM5 controls cardiomyocyte apoptosis induced by MIRI through regulating Keap1-mediated Bcl-xL degradation, which may supply a novel molecular target for acute myocardial infarction (AMI) therapy. Graphical abstract ᅟ.
Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China.
Chen
C
Yang
Department of Pathogen Biology, Medical College, Nantong University, Nantong, Jiangsu, 226001, China.|Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College, Nantong University, Nantong, Jiangsu, 226001, China.
Xiaojuan
X
Liu
Department of Infection Diseases, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China.
Fangfang
F
Yang
Medical College, Nantong University, Nantong, Jiangsu, 226001, China.
Weixun
W
Zhang
Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China.
Zihao
Z
Chen
Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China.
Daliang
D
Yan
Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China. youqs_pro001@sina.com.
Qingsheng
Q
You
Department of Vasculocardiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China. ntwx0513@163.com.
Xiang
X
Wu
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004195:Disease Models, Animal; D034281:Dynamins / Q000096:biosynthesis; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000096:biosynthesis* / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000235:genetics / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D051020:bcl-X Protein / Q000096:biosynthesis* / Q000235:genetics
C494813:Bcl2l1 protein, rat; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D051020:bcl-X Protein; D010749:Phosphoprotein Phosphatases; C519851:Dnm1l protein, rat; D034281:Dynamins
Apoptosis; Bcl-xL; Keap1; Myocardial ischemia/reperfusion; PGAM5