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

Proc Natl Acad Sci U S A. 2010 May 25;107(21):9747-52. doi: 10.1073/pnas.0911175107. Epub 2010 May 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Animals
  • Animals, Genetically Modified
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / cytology
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • Gene Deletion
  • Male
  • Mice
  • Microscopy, Electron
  • Mitochondria / metabolism*
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Peroxiredoxins
  • Protein Deglycase DJ-1
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Spermatogenesis
  • Up-Regulation

Substances

  • DJ-1alpha protein, Drosophila
  • Drosophila Proteins
  • Nerve Tissue Proteins
  • Oncogene Proteins
  • Adenosine Triphosphate
  • Peroxiredoxins
  • PINK1 protein, Drosophila
  • Protein Serine-Threonine Kinases
  • DJ-1beta protein, Drosophila
  • PARK7 protein, mouse
  • Protein Deglycase DJ-1