Mutations or deletions in PARKIN/PARK2, PINK1/PARK6, and DJ-1/ PARK7 lead to autosomal recessive parkinsonism. In Drosophila, deletions in parkin and pink1 result in swollen and dysfunctional mitochondria in energy-demanding tissues. The relationship between DJ-1 and mitochondria, however, remains unclear. We now report that Drosophila and mouse mutants in DJ-1 show compromised mitochondrial function with age. Flies deleted for DJ-1 manifest similar defects as pink1 and parkin mutants: male sterility, shortened lifespan, and reduced climbing ability. We further found poorly coupled mitochondria in vitro and reduced ATP levels in fly and mouse DJ-1 mutants. Surprisingly, up-regulation of DJ-1 can ameliorate pink1, but not parkin, mutants in Drosophila; cysteine C104 (analogous to C106 in human) is critical for this rescue, implicating the oxidative functions of DJ-1 in this property. These results suggest that DJ-1 is important for proper mitochondrial function and acts downstream of, or in parallel to, pink1. These findings link DJ-1, pink1, and parkin to mitochondrial integrity and provide the foundation for therapeutics that link bioenergetics and parkinsonism.parkin | Parkinson's disease | oxidative stress | Drosophila P arkinson's disease (PD) is the most common movement disorder and the second most common neurodegenerative disease. Clinically, it is characterized by resting tremor, rigidity, bradykinesia, gait abnormality, and slow movement (1, 2). PD patients show severe dopaminergic neuron loss, resulting in a decrease of striatal dopamine levels responsible for the motor features (3, 4). Age is the most potent risk factor for PD, but other contributing factors include exposure to environmental toxins like paraquat and rotenone. Although predominantly idiopathic, genetic mutations account for ≈10% of cases (5). Studies of genes responsible for familial parkinsonism/PD are yielding critical insight into mechanisms shared by sporadic and familial disease.Mutations in DJ-1/PARK7, PINK1/PARK6, and PARKIN/PARK2 lead to autosomal recessive parkinsonism. Properties of DJ-1 suggest that it may be at a compelling intersection for several risk factors in PD, including genetics, oxidative stress, environmental factors, and age. First, DJ-1 gene mutations lead to early-onset autosomal recessive parkinsonism (6). Second, the DJ-1 protein is sensitive to oxidative stress and may act as a redox-responsive molecular chaperone that can prevent protein misfolding (7). Third, tolerance toward paraquat in animals is mediated, in part, through modifications of DJ-1 protein (8). Finally, age induces the same modifications of the DJ-1 protein as environmental toxins (8). Mice mutant for DJ-1 show dopamine reuptake dysfunction (9) and have increased sensitivity to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) (10). Two DJ-1 orthologs (DJ-1a and DJ-1b) exist in Drosophila, and when deleted, flies have decreased climbing ability (11) and increased sensitivity to H 2 O 2 , paraquat, and rotenone (12). Taken to...
