Dongworth, R.KMukherjee, U.AHall, A.RAstin, ROng, S.-BYao, ZDyson, ASzabadkai, GDavidson, S.MYellon, D.MHausenloy, D.JDUKE-NUS MEDICAL SCHOOL2020-10-202020-10-202014Dongworth, R.K, Mukherjee, U.A, Hall, A.R, Astin, R, Ong, S.-B, Yao, Z, Dyson, A, Szabadkai, G, Davidson, S.M, Yellon, D.M, Hausenloy, D.J (2014). DJ-1 protects against cell death following acute cardiac ischemiareperfusion injury. Cell Death and Disease 5 (2) : e1082. ScholarBank@NUS Repository. https://doi.org/10.1038/cddis.2014.4120414889https://scholarbank.nus.edu.sg/handle/10635/177770Novel therapeutic targets are required to protect the heart against cell death from acute ischemiareperfusion injury (IRI). Mutations in the DJ-1 (PARK7) gene in dopaminergic neurons induce mitochondrial dysfunction and a genetic form of Parkinson's disease. Genetic ablation of DJ-1 renders the brain more susceptible to cell death following ischemiareperfusion in a model of stroke. Although DJ-1 is present in the heart, its role there is currently unclear. We sought to investigate whether mitochondrial DJ-1 may protect the heart against cell death from acute IRI by preventing mitochondrial dysfunction. Overexpression of DJ-1 in HL-1 cardiac cells conferred the following beneficial effects: reduced cell death following simulated IRI (30.4±4.7% with DJ-1 versus 52.9±4.7% in control; n=5, P<0.05); delayed mitochondrial permeability transition pore (MPTP) opening (a critical mediator of cell death) (260±33 s with DJ-1 versus 121±12 s in control; n=6, P<0.05); and induction of mitochondrial elongation (81.3±2.5% with DJ-1 versus 62.0±2.8% in control; n=6 cells, P<0.05). These beneficial effects of DJ-1 were absent in cells expressing the non-functional DJ-1L166P and DJ-1Cys106A mutants. Adult mice devoid of DJ-1 (KO) were found to be more susceptible to cell death from in vivo IRI with larger myocardial infarct sizes (50.9±3.5% DJ-1 KO versus 41.1±2.5% in DJ-1 WT; n?7, P<0.05) and resistant to cardioprotection by ischemic preconditioning. DJ-1 KO hearts showed increased mitochondrial fragmentation on electron microscopy, although there were no differences in calcium-induced MPTP opening, mitochondrial respiratory function or myocardial ATP levels. We demonstrate that loss of DJ-1 protects the heart from acute IRI cell death by preventing mitochondrial dysfunction. We propose that DJ-1 may represent a novel therapeutic target for cardioprotection. © 2014 Macmillan Publishers Limited.Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/1,2,3,6 tetrahydro 1 methyl 4 phenylpyridineadenosine triphosphatecalciumDJ 1 proteinmitochondrial permeability transition poreadultanimal experimentanimal modelanimal tissuearticlecell deathcell protectioncell survivalcontrolled studydisease predispositionechocardiographyelectron microscopygene overexpressionheart infarction preventionheart infarction sizeheart mitochondrionknockout genemitochondrial membrane potentialmitochondrial respirationmitochondrion swellingmousemutantnonhumanphenotypepriority journalreperfusion injurysarcomere lengthwild typeAdenosine TriphosphateAnimalsCalciumCell DeathCell LineDisease Models, AnimalIschemic Preconditioning, MyocardialMiceMice, Inbred C57BLMice, KnockoutMitochondria, HeartMitochondrial Membrane Transport ProteinsMyocardial InfarctionMyocardial Reperfusion InjuryMyocardiumMyocytes, CardiacOncogene ProteinsTransfectionArticle