Mitochondria structural determinants of function19Mitochondrial DJ-1 as a target for cardioprotection

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Abstract

Purpose

Mutations in the DJ-1 gene are a cause of familial Parkinson's disease. Dopaminergic neurones deficient in DJ-1 have impaired mitochondrial function and are more susceptible to oxidative stress and apoptotic cell death. DJ-1 is present in the heart but its role there is unknown. Given its beneficial effects on mitochondrial function in neuronal tissue, we hypothesised that DJ-1 protects the heart against acute ischaemia-reperfusion injury (IRI).

Methods

Western blots were undertaken to investigate the expression of DJ-1 in the murine cardiac HL-1 cell line. HL-1 cells were transfected with either empty vector, wild-type DJ-1, mitochondrial-targeted DJ-1, the Cys106A DJ-1 mutant (which is unable to oxidise Cys106, required for DJ-1 activation) or the L166P DJ-1 mutant DJ-1 (which is unable to dimerise and translocate to mitochondria) and the effects on mitochondrial morphology (Mitofusin 1, Mfn1, used as positive control for mitochondrial elongation), the susceptibility to mitochondrial permeability transition pore (mPTP) opening (Cyclosporin A, CsA, used as mPTP inhibitor positive control), and cell survival following simulated IRI, were investigated.

Results

The overexpression of DJ-1 in the HL-1 cardiac cell line resulted in: (1) a significant increase in the proportion of HL-1 cells displaying elongated mitochondria (71.7n ± 5.1% with DJ-1 and 73.4n ± 4.1% with Mfn1 vs 56.0n ± 2.6% with control; N=60 cells/group; P < 0.05); (2) a significant reduction in cell death (19.4n ± 3.4% with DJ-1 and 16.6n ± 5.0% with insulin vs 35.0n ± 4.2% with control N=640/group: P < 0.05); (3) a significant delay in the time taken to induce mPTP opening (2.7n ± 0.4 fold increase with DJ-1 and 3.0n ± 0.6 fold increase with CsA vs control; N=80 cells/group; P < 0.05). These beneficial effects of wild type DJ-1 on mitochondrial function were less pronounced in both the Cys106A and L166P DJ-1 mutants.

Conclusion

We show a novel role for DJ-1 in the heart. It appears to protect the heart from IRI and this effect is associated with mitochondrial elongation and mPTP inhibition. The cardioprotective effect of DJ-1 appears to be dependant on Cys106 and dimerization. Experimental studies are now underway to investigate the effects of DJ-1 ablation in the adult heart on the susceptibility to IRI.

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