Loss of the Parkinson's disease-linked gene DJ-1 perturbs mitochondrial dynamics.
Growing evidence highlights a role for mitochondrial dysfunction and oxidative stress as underlying contributors to Parkinson's disease (PD) pathogenesis. DJ-1 (PARK7) is a recently identified recessive familial PD gene. Its loss leads to increased susceptibility of neurons to oxidative stress and death. However, its mechanism of action is not fully understood. Presently, we report that DJ-1 deficiency in cell lines, cultured neurons, mouse brain and lymphoblast cells derived from DJ-1 patients display aberrant mitochondrial morphology. We also show that these DJ-1-dependent mitochondrial defects contribute to oxidative stress-induced sensitivity to cell death since reversal of this fragmented mitochondrial phenotype abrogates neuronal cell death. Reactive oxygen species (ROS) appear to play a critical role in the observed defects, as ROS scavengers rescue the phenotype and mitochondria isolated from DJ-1 deficient animals produce more ROS compared with control. Importantly, the aberrant mitochondrial phenotype can be rescued by the expression of Pink1 and Parkin, two PD-linked genes involved in regulating mitochondrial dynamics and quality control. Finally, we show that DJ-1 deficiency leads to altered autophagy in murine and human cells. Our findings define a mechanism by which the DJ-1-dependent mitochondrial defects contribute to the increased sensitivity to oxidative stress-induced cell death that has been previously reported.
Irrcher
I
I
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
Aleyasin
H
H
Seifert
E L
EL
Hewitt
S J
SJ
Chhabra
S
S
Phillips
M
M
Lutz
A K
AK
Rousseaux
M W C
MW
Bevilacqua
L
L
Jahani-Asl
A
A
Callaghan
S
S
MacLaurin
J G
JG
Winklhofer
K F
KF
Rizzu
P
P
Rippstein
P
P
Kim
R H
RH
Chen
C X
CX
Fon
E A
EA
Slack
R S
RS
Harper
M E
ME
McBride
H M
HM
Mak
T W
TW
Park
D S
DS
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics* / Q000473:pathology* / Q000648:ultrastructure; D050505:Mutant Proteins / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D015513:Oncogene Proteins / Q000172:deficiency* / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D054464:Peroxiredoxins; D010641:Phenotype; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
D000111:Acetylcysteine; D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D015513:Oncogene Proteins; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D017382:Reactive Oxygen Species; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C105131:PARK7 protein, human; C503466:PARK7 protein, mouse