Mutations in DJ-1/PARK7 (Parkinson protein 7) have been identified as a cause of autosomal-recessive PD (Parkinson's disease) and the antioxidant property of DJ-1 has been shown to be involved in the regulation of mitochondrial function and neuronal cell survival. In the present study, we first found that the DJ-1 transgene mitigated MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced DA (dopamine) neuron cell death and cell loss. We then observed that the protein levels of DJ-1 were significantly decreased, whereas levels of Fis1 [fission 1 (mitochondrial outer membrane) homologue] were noticeably increased in the striatum of MPTP-treated mice. In addition to our identification of RNF5 (RING-finger protein-5) as an E3-ligase for Fis1 ubiquitination, we demonstrated the involvement of the DJ-1/Akt/RNF5 signalling pathway in the regulation of Fis1 proteasomal degradation. In other experiments, we found that Akt1 enhances the mitochondrial translocation and E3-ligase activity of RNF5, leading to Fis1 degradation. Together, the identification of Fist degradation by DJ-1 signalling in the regulation of oxidative stress-induced neuronal cell death supplies a novel mechanism of DJ-1 in neuronal protection with the implication of DJ-1 in a potential therapeutic avenue for PD.