Parkinson\'s disease (PD) is the most common neurodegenerative movement disorder.Mutations in the DJ-1,including L166P,are responsible for recessive earlyonset PD.Many lines of evidence have shown that L166P is not only a loss-of-function mutant,but also a proapoptotic-like protein that results in mitochondrial dysfunction.L166P has been reported to be unstable and to mislocalize to mitochondria.However,the mechanisms underlying the instability of L166P compared to wild-type D J-1 remain largely unknown.Here,we showed that Omi/HtrA2,a mitochondrial serine protease that has also been linked to the pathogenesis of PD,contributed to L166P instability.Omi directly interacted with and cleaved L166P in mitochondria to decrease the L166P level.However,Omi did not bind and cleave wild-type DJ-1.Moreover,Omi cleaved L166P at both serine residues 3 and 121,while L 166P-induced cell death under H2O2 treatment was alleviated by over-expression of Omi.Our data reveal a bridge between DJ-1 and Omi,two PD-associated genetic factors,which contributes to our understanding of the pathogenesis of PD.