Parkin, a ring between ring fingers E3 ubiquitin ligase with a ubiquitin-like domain at the N-terminus, its mutations cause a familial form of Parkinson's disease (PD) known as autosomal recessive juvenile parkinsonism. Recently a series of reports revealed parkin plays an important role in mitochondrial quality control. When the mitochondria are depolarized, parkin is recruited from the cytosol to mitochondria, activated, and ubiquitinates proteins on mitochondrial outer membrane, which leads to mitochondrial degradation via an autophagic event known as mitophagy. It is well-establised how parkin is recruited to depolarized mitochondria, however, molecular mechanism to regulate the activity of parkin is not well-understood.
We hypothesized that the activity of parkin might be regulated by S-nitrosylation, the covalent incorporation of a nitric oxide moiety into thiol groups. S-nitrosylation is enhanced in brain tissues of patients with PD and cultured cells treated with the mitochondrial respiratory chain complex I, however, its pathophysiological significance is still controversial. Here we identified a S-nitrosylated cysteine residue in parkin, and revealed S-nitrosylation of parkin increases E3 ligase activity by comparing with cysteine-to-serine mutant. Furthermore we revealed S-nitrosylation of parkin plays an important role in degradation of depolarized mitochondria. Finally we showed peroxynitrite, which is produced by the reaction of nitric oxide with superoxide, denitrosylated and nitrated parkin and decreased mitochondrial degradation, which can account for the negative effect of NO on mitochondrial quality control. We would propose that our results provide insight that S-nitrosylation plays important roles in mitochondrial quality control, which is possibly involved in the pathogenesis of PD.