DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function

Abstract

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...

Silent Information Regulator 2 (Sir2) and Forkhead Box O (FOXO) Complement Mitochondrial Dysfunction and Dopaminergic Neuron Loss in Drosophila PTEN-induced Kinase 1 (PINK1) Null Mutant

“…In addition, loss of Drosophila phosphoglycerate mutase 5 (PGAM5) gene successfully suppressed mitochondrial degeneration in PINK1 mutants, but failed to modulate the phenotypes induced by loss of parkin (23). Furthermore, up-regulation of DJ-1 can ameliorate PINK1, but not parkin, Drosophila mutants (24). These results suggest that PINK1 can protect mitochondria and cells using other signaling molecules in addition to Parkin.…”

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

“…These data suggest that PGAM5 functions between PINK1 and Parkin or acts downstream of PINK1 parallel to Parkin (Imai et al, 2010). Another Drosophila genetic analysis shows that DJ-1 overexpression can ameliorate PINK1 mutant phenotypes but cannot rescue parkin phenotypes (Hao et al, 2010). However, PINK1 or Parkin overexpression rescues the aberrant mitochondrial phenotype in DJ-1-deficient cells, but DJ-1 does not reduce the mitochondrial fragmentation induced by PINK1 deficiency.…”

Consequences of DJ-1 upregulation following p53 loss and cell transformation

“…DJ-1 (CAP1/RS/PARK7) is a protein described as a protector against oxidative stress in neurons, and is largely documented for its association with Parkinson's disease (Kahle et al, 2009;Aleyasin et al, 2010;Giaime et al, 2010;Guzman et al, 2010;Hao et al, 2010). DJ-1 is also referred to as an oncogene and found to be overexpressed in many types of tumors (Hinkle et al, 2011).…”