title: DJ-1 protects against cell death following acute cardiac ischemia-reperfusion injury.
abstract: Novel therapeutic targets are required to protect the heart against cell death from acute ischemia-reperfusion 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 ischemia-reperfusion 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-1(L166P) and DJ-1(Cys106A) 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.
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, UK.
authors.forename: R K
authors.initials: RK
authors.lastname: Dongworth
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, UK.
authors.forename: U A
authors.initials: UA
authors.lastname: Mukherjee
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Hall
authors.affiliation: Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Astin
authors.affiliation: 1] The Hatter Cardiovascular Institute, University College London, London, UK [2] Department of Clinical Sciences, Faculty of Biosciences and Medical Engineering, Satellite Building V01, Universiti Teknologi Malaysia, Johor Bahru 81310 UTM, Malaysia.
authors.forename: S-B
authors.initials: SB
authors.lastname: Ong
authors.affiliation: Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK.
authors.forename: Z
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Medicine, University College London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Dyson
authors.affiliation: Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Szabadkai
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Davidson
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Yellon
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Hausenloy
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D004195:Disease Models, Animal; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D014162:Transfection
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015513:Oncogene Proteins; D000255:Adenosine Triphosphate; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D002118:Calcium