DJ-1 protects the heart against ischemia-reperfusion injury by regulating mitochondrial fission.
Recent data indicates that DJ-1 plays a role in the cellular response to stress. Here, we aimed to examine the underlying molecular mechanisms mediating the actions of DJ-1 in the heart following myocardial ischemia-reperfusion (I/R) injury. In response to I/R injury, DJ-1 KO mice displayed increased areas of infarction and worsened left ventricular function when compared to WT mice, confirming a protective role for DJ-1 in the heart. In an effort to evaluate the potential mechanism(s) responsible for the increased injury in DJ-1 KO mice, we focused on SUMOylation, a post-translational modification process that regulates various aspects of protein function. DJ-1 KO hearts after I/R injury were found to display enhanced accumulation of SUMO-1 modified proteins and reduced SUMO-2/3 modified proteins. Further analysis, revealed that the protein expression of the de-SUMOylation enzyme SENP1 was reduced, whereas the expression of SENP5 was enhanced in DJ-1 KO hearts after I/R injury. Finally, DJ-1 KO hearts were found to display enhanced SUMO-1 modification of dynamin-related protein 1, excessive mitochondrial fission, and dysfunctional mitochondria. Our data demonstrates that the activation of DJ-1 in response to myocardial I/R injury protects the heart by regulating the SUMOylation status of Drp1 and attenuating excessive mitochondrial fission.
Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA, USA.
Yuuki
Y
Shimizu
Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA, USA.
Jonathan P
JP
Lambert
Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA, USA.
Chad K
CK
Nicholson
Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA, USA.
Joshua J
JJ
Kim
Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
David W
DW
Wolfson
Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
Hee Cheol
HC
Cho
Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.
Ahsan
A
Husain
Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.
Nawazish
N
Naqvi
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
Li-Shen
LS
Chin
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
Lian
L
Li
Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA, USA. Electronic address: jcalver@emory.edu.
John W
JW
Calvert
D000818:Animals; D001706:Biopsy; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000235:genetics* / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000235:genetics*; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress; D000071617:Protein Deglycase DJ-1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D059748:Proteolysis; D051381:Rats; D017382:Reactive Oxygen Species; D058207:Sumoylation
D017382:Reactive Oxygen Species; D000071617:Protein Deglycase DJ-1
DJ-1; Mitochondrial fission; Myocardial ischemia; SUMOylation