DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function.
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.
Hao
Ling-Yang
LY
Department of Biology, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Giasson
Benoit I
BI
Bonini
Nancy M
NM
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D030801:Animals, Genetically Modified; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013091:Spermatogenesis; D015854:Up-Regulation; D000099202:PTEN-Induced Putative Kinase
D000255:Adenosine Triphosphate; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D017346:Protein Serine-Threonine Kinases; C506878:DJ-1alpha protein, Drosophila; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C506879:DJ-1beta protein, Drosophila; C503466:PARK7 protein, mouse
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