DJ-1 Protects the Heart Against Ischemia-reperfusion Injury by Regulating Mitochondrial Fission

Overview

Journal J Mol Cell Cardiol

Specialty Cardiology & Vascular Diseases

Date 2016 Apr 26

PMID 27108530

Citations 55

Authors

Yuuki Shimizu

Jonathan P Lambert

Chad K Nicholson

Joshua J Kim

David W Wolfson

Hee Cheol Cho

Ahsan Husain

Nawazish Naqvi

Li-Shen Chin

Lian Li

John W Calvert

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

DJ-1 as a Novel Therapeutic Target for Mitigating Myocardial Ischemia-Reperfusion Injury.

Zhou J, Wei T, Wu D, Zhou F, Wang R Cardiovasc Ther. 2025; 2024:6615720.

PMID: 39742003 PMC: 11661871. DOI: 10.1155/cdr/6615720.

Effects of Pterostilbene on Cardiovascular Health and Disease.

Tian R, Miao L, Cheang W Curr Issues Mol Biol. 2024; 46(9):9576-9587.

PMID: 39329921 PMC: 11430207. DOI: 10.3390/cimb46090569.

Targeting mitochondrial quality control: new therapeutic strategies for major diseases.

Hong W, Huang H, Zeng X, Duan C Mil Med Res. 2024; 11(1):59.

PMID: 39164792 PMC: 11337860. DOI: 10.1186/s40779-024-00556-1.

Effects of protein glycation and protective mechanisms against glycative stress.

Najjar J, Calvert J Curr Opin Pharmacol. 2024; 76:102464.

PMID: 38796877 PMC: 11229435. DOI: 10.1016/j.coph.2024.102464.

The Dynamic SUMOylation Changes and Their Potential Role in the Senescence of APOE4 Mice.

Xu Y, Cai W, Sang S, Cheng X, Jin B, Zhao X Biomedicines. 2024; 12(1).

PMID: 38275378 PMC: 10813299. DOI: 10.3390/biomedicines12010016.

References

Wang J, Chen L, Wen S, Zhu H, Yu W, Moskowitz I . Defective sumoylation pathway directs congenital heart disease. Birth Defects Res A Clin Mol Teratol. 2011; 91(6):468-76. PMC: 5031480. DOI: 10.1002/bdra.20816. View

Kim E, Zhang Y, Beketaev I, Segura A, Yu W, Xi Y . SENP5, a SUMO isopeptidase, induces apoptosis and cardiomyopathy. J Mol Cell Cardiol. 2014; 78:154-64. DOI: 10.1016/j.yjmcc.2014.08.003. View

Zhang Y, Sarge K . Sumoylation regulates lamin A function and is lost in lamin A mutants associated with familial cardiomyopathies. J Cell Biol. 2008; 182(1):35-9. PMC: 2447889. DOI: 10.1083/jcb.200712124. View

Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A . DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol. 2004; 2(11):e362. PMC: 521177. DOI: 10.1371/journal.pbio.0020362. View

Chen J, Li L, Chin L . Parkinson disease protein DJ-1 converts from a zymogen to a protease by carboxyl-terminal cleavage. Hum Mol Genet. 2010; 19(12):2395-408. PMC: 2876885. DOI: 10.1093/hmg/ddq113. View

Wang X, Petrie T, Liu Y, Liu J, Fujioka H, Zhu X . Parkinson's disease-associated DJ-1 mutations impair mitochondrial dynamics and cause mitochondrial dysfunction. J Neurochem. 2012; 121(5):830-9. PMC: 3740560. DOI: 10.1111/j.1471-4159.2012.07734.x. View

Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K, Ariga H . DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem Biophys Res Commun. 1997; 231(2):509-13. DOI: 10.1006/bbrc.1997.6132. View

Guo C, Hildick K, Luo J, Dearden L, Wilkinson K, Henley J . SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia. EMBO J. 2013; 32(11):1514-28. PMC: 3671254. DOI: 10.1038/emboj.2013.65. View

Yang W, Sheng H, Warner D, Paschen W . Transient global cerebral ischemia induces a massive increase in protein sumoylation. J Cereb Blood Flow Metab. 2007; 28(2):269-79. DOI: 10.1038/sj.jcbfm.9600523. View

10.

Wang J, Schwartz R . Sumoylation and regulation of cardiac gene expression. Circ Res. 2010; 107(1):19-29. PMC: 3744328. DOI: 10.1161/CIRCRESAHA.110.220491. View

11.

Yu T, Fox R, Burwell L, Yoon Y . Regulation of mitochondrial fission and apoptosis by the mitochondrial outer membrane protein hFis1. J Cell Sci. 2005; 118(Pt 18):4141-51. DOI: 10.1242/jcs.02537. View

12.

Kim E, Chen L, Ma Y, Yu W, Chang J, Moskowitz I . Enhanced desumoylation in murine hearts by overexpressed SENP2 leads to congenital heart defects and cardiac dysfunction. J Mol Cell Cardiol. 2011; 52(3):638-49. PMC: 3294171. DOI: 10.1016/j.yjmcc.2011.11.011. View

13.

Wang J, Jiao J, Li Q, Long B, Wang K, Liu J . miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1. Nat Med. 2010; 17(1):71-8. DOI: 10.1038/nm.2282. View

14.

Gareau J, Lima C . The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol. 2010; 11(12):861-71. PMC: 3079294. DOI: 10.1038/nrm3011. View

15.

Dhingra R, Kirshenbaum L . Regulation of mitochondrial dynamics and cell fate. Circ J. 2014; 78(4):803-10. DOI: 10.1253/circj.cj-14-0240. View

16.

Frank S, Gaume B, Bergmann-Leitner E, Leitner W, Robert E, Catez F . The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell. 2001; 1(4):515-25. DOI: 10.1016/s1534-5807(01)00055-7. View

17.

Taira T, Saito Y, Niki T, Iguchi-Ariga S, Takahashi K, Ariga H . DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep. 2004; 5(2):213-8. PMC: 1298985. DOI: 10.1038/sj.embor.7400074. View

18.

Zhong N, Kim C, Rizzu P, Geula C, Porter D, Pothos E . DJ-1 transcriptionally up-regulates the human tyrosine hydroxylase by inhibiting the sumoylation of pyrimidine tract-binding protein-associated splicing factor. J Biol Chem. 2006; 281(30):20940-20948. DOI: 10.1074/jbc.M601935200. View

19.

Dongworth R, Mukherjee U, Hall A, Astin R, Ong S, Yao Z . DJ-1 protects against cell death following acute cardiac ischemia-reperfusion injury. Cell Death Dis. 2014; 5:e1082. PMC: 3944257. DOI: 10.1038/cddis.2014.41. View

20.

Hay R . SUMO-specific proteases: a twist in the tail. Trends Cell Biol. 2007; 17(8):370-6. DOI: 10.1016/j.tcb.2007.08.002. View