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The role of cysteine oxidation in DJ-1 function and dysfunction.

ABSTRACT: DJ-1 is a member of the large and functionally diverse DJ-1/PfpI superfamily and has homologs in nearly all organisms. Because of its connection to parkinsonism and cancer, human DJ-1 has been intensely studied for over a decade. The current view is that DJ-1 is a multifunctional oxidative stress response protein that defends cells against reactive oxygen species and mitochondrial damage, although the details of its biochemical function remain unclear. A conserved cysteine residue in DJ-1 (Cys106) is both functionally essential and subject to oxidation to the cysteine-sulfinate and cysteine-sulfonate. Consequently, the oxidative modification of Cys106 has been proposed to allow DJ-1 to act as a sensor of cellular redox homeostasis and to participate in cytoprotective signaling pathways in the cell. This review explores the current evidence for the role of cysteine oxidation in DJ-1 function, with emphasis on emerging models for how oxidative modification may regulate DJ-1's protective function and also contribute to dysfunction and disease.

SUBMITTER: Wilson MA

PROVIDER: S-EPMC3110098 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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The role of cysteine oxidation in DJ-1 function and dysfunction.

Wilson Mark A MA

Antioxidants & redox signaling 20110114 1

DJ-1 is a member of the large and functionally diverse DJ-1/PfpI superfamily and has homologs in nearly all organisms. Because of its connection to parkinsonism and cancer, human DJ-1 has been intensely studied for over a decade. The current view is that DJ-1 is a multifunctional oxidative stress response protein that defends cells against reactive oxygen species and mitochondrial damage, although the details of its biochemical function remain unclear. A conserved cysteine residue in DJ-1 (Cys10 ...[more]

PMID: 20812780

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Project description:Mitochondrial dysfunction has long been implicated in the pathogenesis of Parkinson's disease (PD). PD brain tissues show evidence for mitochondrial respiratory chain Complex I deficiency. Pharmacological inhibitors of Complex I, such as rotenone, cause experimental parkinsonism. The cytoprotective protein DJ-1, whose deletion is sufficient to cause genetic PD, is also known to have mitochondria-stabilizing properties. We have previously shown that DJ-1 is over-expressed in PD astrocytes, and that DJ-1 deficiency impairs the capacity of astrocytes to protect co-cultured neurons against rotenone. Since DJ-1 modulated, astrocyte-mediated neuroprotection against rotenone may depend upon proper astrocytic mitochondrial functioning, we hypothesized that DJ-1 deficiency would impair astrocyte mitochondrial motility, fission/fusion dynamics, membrane potential maintenance, and respiration, both at baseline and as an enhancement of rotenone-induced mitochondrial dysfunction. In astrocyte-enriched cultures, we observed that DJ-1 knock-down reduced mitochondrial motility primarily in the cellular processes of both untreated and rotenone treated cells. In these same cultures, DJ-1 knock-down did not appreciably affect mitochondrial fission, fusion, or respiration, but did enhance rotenone-induced reductions in the mitochondrial membrane potential. In neuron-astrocyte co-cultures, astrocytic DJ-1 knock-down reduced astrocyte process mitochondrial motility in untreated cells, but this effect was not maintained in the presence of rotenone. In the same co-cultures, astrocytic DJ-1 knock-down significantly reduced mitochondrial fusion in the astrocyte cell bodies, but not the processes, under the same conditions of rotenone treatment in which DJ-1 deficiency is known to impair astrocyte-mediated neuroprotection. Our studies therefore demonstrated the following new findings: (i) DJ-1 deficiency can impair astrocyte mitochondrial physiology at multiple levels, (ii) astrocyte mitochondrial dynamics vary with sub-cellular region, and (iii) the physical presence of neurons can affect astrocyte mitochondrial behavior.

Dataset Information

The role of cysteine oxidation in DJ-1 function and dysfunction.

Publications

The role of cysteine oxidation in DJ-1 function and dysfunction.

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