DJ-1 protects against cell death following acute cardiac ischemiareperfusion injury
Dongworth, 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
Dongworth, R.K
Mukherjee, U.A
Hall, A.R
Astin, R
Yao, Z
Dyson, A
Szabadkai, G
Davidson, S.M
Yellon, D.M
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Alternative Title
Abstract
Novel 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.
Keywords
1,2,3,6 tetrahydro 1 methyl 4 phenylpyridine, adenosine triphosphate, calcium, DJ 1 protein, mitochondrial permeability transition pore, adult, animal experiment, animal model, animal tissue, article, cell death, cell protection, cell survival, controlled study, disease predisposition, echocardiography, electron microscopy, gene overexpression, heart infarction prevention, heart infarction size, heart mitochondrion, knockout gene, mitochondrial membrane potential, mitochondrial respiration, mitochondrion swelling, mouse, mutant, nonhuman, phenotype, priority journal, reperfusion injury, sarcomere length, wild type, Adenosine Triphosphate, Animals, Calcium, Cell Death, Cell Line, Disease Models, Animal, Ischemic Preconditioning, Myocardial, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Heart, Mitochondrial Membrane Transport Proteins, Myocardial Infarction, Myocardial Reperfusion Injury, Myocardium, Myocytes, Cardiac, Oncogene Proteins, Transfection
Source Title
Cell Death and Disease
Publisher
Series/Report No.
Collections
Rights
Attribution 4.0 International
Date
2014
DOI
10.1038/cddis.2014.41
Type
Article