DJ-1 protects against cell death following acute cardiac ischemia–reperfusion injury

R K Dongworth,S-B Ong,U A Mukherjee,G Szabadkai,S M Davidson,A R Hall,D J Hausenloy,D M Yellon,R Astin,Z Yao,A Dyson

doi:10.1038/cddis.2014.41

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-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.

Highlights

DJ-1 ( known as PARK7 (Parkinson disease 7)) is a widely expressed and conserved mitochondrial protein that has been implicated in numerous pathologies, most notably in neurodegeneration where mutations in DJ-1
We demonstrate that mitochondrial DJ-1 may be an important therapeutic target for cardioprotection as evidenced by the following:(1) overexpression of WT DJ-1 but not its mutant forms reduced cell death following simulated ischemia–reperfusion injury (IRI), delayed mitochondrial permeability transition pore (MPTP) opening, and induced mitochondrial elongation in the HL-1 cardiac cell line; and (2) adult murine hearts deficient in DJ-1 were found to be more susceptible to cell death from IRI as evidenced by a larger myocardial infarct (MI) size, a finding which was associated with increased mitochondrial fragmentation
The beneficial effects of WT DJ-1 overexpression in HL-1 cells observed in our study appeared to be dependent on the ability of DJ-1 to dimerize and sense oxidation, as these effects were absent with the mutant forms of the protein, DJ-1L166P and DJ-1Cys106A

Summary

Introduction

DJ-1 ( known as PARK7 (Parkinson disease (autosomal recessive, early onset) 7)) is a widely expressed and conserved mitochondrial protein that has been implicated in numerous pathologies, most notably in neurodegeneration where mutations in DJ-1 L166P mutation) result in an early-onset familial form of Parkinson’s disease.[1] Several experimental studies have elucidated important properties for DJ-1, including oxidative stress sensing, reactive oxygen species scavenging[2,3,4] and preservation of normal mitochondrial function in the brain.[2,5,6] Given its crucial role in maintaining mitochondrial function, DJ-1 represents a potential target for novel therapies for other pathologies involving mitochondrial dysfunction and cell death, including IRI. Animal studies have shown that DJ-1 ablation renders the brain more susceptible to cell death in the setting of stroke.[7] DJ-1 is expressed in the heart,[1] its role there is not well understood. We investigated the role of mitochondrial DJ-1 in the heart and its potential as a novel therapeutic target for protecting the heart against cell death following acute IRI

Methods

Results

Conclusion