The protein DJ-1 is neuroprotective in Parkinson's disease (PD) due to a posttranslational modification involving cysteine-sulfinic acid. Loss-of-function mutations in DJ-1 cause early-onset PD, and its function remains unclear. However, an acidic isoform of DJ-1 accumulates under oxidative stress, suggesting a protective role. This study shows that DJ-1 is oxidized at cysteine residue C106, forming cysteine-sulfinic acid, which is crucial for its mitochondrial localization and neuroprotective function. Mutating C106 to alanine (C106A) prevents oxidation, mitochondrial relocalization, and protection against cell death, indicating that C106's oxidation is essential for DJ-1's protective effects. DJ-1 is also responsive to oxidative stress, with a shift in isoelectric point (pI) from 6.2 to 5.8. In PD brains, acidic forms of DJ-1 accumulate, but the nature of these modifications is unclear. The study confirms that C106 is oxidized to cysteine-sulfinic acid, which is important for DJ-1's function. DJ-1 protects neurons against oxidative stress and mitochondrial damage, and its protective role is signaled by the oxidation of C106. The study also shows that DJ-1 can be targeted to mitochondria under certain conditions, and that C106 is a key residue for this process. The findings suggest that DJ-1's neuroprotective function is regulated by the oxidation of C106, which is a reversible posttranslational modification. This study provides insights into the molecular mechanisms underlying DJ-1's protective role in PD.The protein DJ-1 is neuroprotective in Parkinson's disease (PD) due to a posttranslational modification involving cysteine-sulfinic acid. Loss-of-function mutations in DJ-1 cause early-onset PD, and its function remains unclear. However, an acidic isoform of DJ-1 accumulates under oxidative stress, suggesting a protective role. This study shows that DJ-1 is oxidized at cysteine residue C106, forming cysteine-sulfinic acid, which is crucial for its mitochondrial localization and neuroprotective function. Mutating C106 to alanine (C106A) prevents oxidation, mitochondrial relocalization, and protection against cell death, indicating that C106's oxidation is essential for DJ-1's protective effects. DJ-1 is also responsive to oxidative stress, with a shift in isoelectric point (pI) from 6.2 to 5.8. In PD brains, acidic forms of DJ-1 accumulate, but the nature of these modifications is unclear. The study confirms that C106 is oxidized to cysteine-sulfinic acid, which is important for DJ-1's function. DJ-1 protects neurons against oxidative stress and mitochondrial damage, and its protective role is signaled by the oxidation of C106. The study also shows that DJ-1 can be targeted to mitochondria under certain conditions, and that C106 is a key residue for this process. The findings suggest that DJ-1's neuroprotective function is regulated by the oxidation of C106, which is a reversible posttranslational modification. This study provides insights into the molecular mechanisms underlying DJ-1's protective role in PD.