Parkinson's disease-associated DJ-1 mutations impair mitochondrial dynamics and cause mitochondrial dysfunction

Xinglong Wang, Timothy G. Petrie, Yingchao Liu, Jun Liu, Hisashi Fujioka, Xiongwei Zhu

Research output: Contribution to journalArticlepeer-review

144 Scopus citations

Abstract

Mitochondrial dysfunction represents a critical event during the pathogenesis of Parkinson's disease (PD) and expanding evidences demonstrate that an altered balance in mitochondrial fission/fusion is likely an important mechanism leading to mitochondrial and neuronal dysfunction/degeneration. In this study, we investigated whether DJ-1 is involved in the regulation of mitochondrial dynamics and function in neuronal cells. Confocal and electron microscopic analysis demonstrated that M17 human neuroblastoma cells over-expressing wild-type DJ-1 (WT DJ-1 cells) displayed elongated mitochondria while M17 cells over-expressing PD-associated DJ-1 mutants (R98Q, D149A and L166P) (mutant DJ-1 cells) showed significant increase of fragmented mitochondria. Similar mitochondrial fragmentation was also noted in primary hippocampal neurons over-expressing PD-associated mutant forms of DJ-1. Functional analysis revealed that over-expression of PD-associated DJ-1 mutants resulted in mitochondria dysfunction and increased neuronal vulnerability to oxidative stress (H 2O 2) or neurotoxin. Further immunoblot studies demonstrated that levels of dynamin-like protein (DLP1), also known as Drp1, a regulator of mitochondrial fission, was significantly decreased in WT DJ-1 cells but increased in mutant DJ-1 cells. Importantly, DLP1 knockdown in these mutant DJ-1 cells rescued the abnormal mitochondria morphology and all associated mitochondria/neuronal dysfunction. Taken together, these studies suggest that DJ-1 is involved in the regulation of mitochondrial dynamics through modulation of DLP1 expression and PD-associated DJ-1 mutations may cause PD by impairing mitochondrial dynamics and function. Abnormal mitochondrial dynamics is implicated in neurodegenerative diseases. We found that expression of PD-associated DJ-1 mutants resulted in excessive mitochondrial fragmentation via increased DLP1 expression, which in turn leads to mitochondrial dysfunction and increased neuronal susceptibility to H 2O 2 or MPP +. Expression of WT DJ-1 caused mitochondrial elongation and protection. These studies suggest that impaired mitochondrial dynamics underlies neuronal dysfunction/degeneration caused by DJ-1 mutations.

Original languageEnglish (US)
Pages (from-to)830-839
Number of pages10
JournalJournal of Neurochemistry
Volume121
Issue number5
DOIs
StatePublished - Jun 2012
Externally publishedYes

Keywords

  • DJ-1
  • Drp1
  • Parkinson disease
  • mitochondrial elongation
  • mitochondrial fragmentation
  • mitochondrial fusion

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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