Glutathione in Parkinson's disease: A link between oxidative stress and mitochondrial damage?

Monte, Donato A. Di; Chan, Piu; Sandy, Martha S.

doi:10.1002/ana.410320719

Cited by 98 publications

(56 citation statements)

References 27 publications

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“…It has been proposed that the downregulation of GSH observed in PD is associated with mitochondrial damage caused by oxidative stress and that this decrease in GSH accelerates the death of dopaminergic neurons (26). Consistent with this finding, we found that depletion of Pink1 in lymphocytes via shRNA treatment led to a dramatic decrease in GSH that sensitized T cells to death caused by IL-2 withdrawal.…”

Section: Discussionsupporting

confidence: 90%

FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation

Mei

Zhang²,

Yamamoto³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

151

138

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Section: Discussionsupporting

confidence: 90%

FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation

Mei

Zhang²,

Yamamoto³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

151

138

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“…Instead the duration of exposure to an oxidized GSH/GSSG ratio was critical for inactivation. These changes in complex I activity are of considerable pathological significance as the selective loss of complex I activity in the substantia nigra of brains from Parkinson's disease patients is associated with oxidation of the glutathione pool (47,48).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its action as a redox coupled proton pump, complex I is a major source of ROS within the cell (49), is involved in the mitochondrial permeability transition (50), is particularly susceptible to inactivation during degenerative diseases and other pathologies (47,48) and is also involved in early mitochondrial changes during apoptosis (51). The central role of complex I in mitochondria suggests that the Grx2-catalyzed glutathionylation of complex I in response to slight oxidation of the mitochondrial glutathione pool may have physiological significance.…”

Section: Discussionmentioning

confidence: 99%

Glutaredoxin 2 Catalyzes the Reversible Oxidation and Glutathionylation of Mitochondrial Membrane Thiol Proteins

Beer

Taylor

Brown

et al. 2004

Journal of Biological Chemistry

371

350

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The redox poise of the mitochondrial glutathione pool is central in the response of mitochondria to oxidative damage and redox signaling, but the mechanisms are uncertain. One possibility is that the oxidation of glutathione (GSH) to glutathione disulfide (GSSG) and the consequent change in the GSH/GSSG ratio causes protein thiols to change their redox state, enabling protein function to respond reversibly to redox signals and oxidative damage. However, little is known about the interplay between the mitochondrial glutathione pool and protein thiols. Therefore we investigated how physiological GSH/GSSG ratios affected the redox state of mitochondrial membrane protein thiols. Exposure to oxidized GSH/GSSG ratios led to the reversible oxidation of reactive protein thiols by thiol-disulfide exchange, the extent of which was dependent on the GSH/GSSG ratio. There was an initial rapid phase of protein thiol oxidation, followed by gradual oxidation over 30 min. A large number of mitochondrial proteins contain reactive thiols and most of these formed intraprotein disulfides upon oxidation by GSSG; however, a small number formed persistent mixed disulfides with glutathione. Both protein disulfide formation and glutathionylation were catalyzed by the mitochondrial thiol transferase glutaredoxin 2 (Grx2), as were protein deglutathionylation and the reduction of protein disulfides by GSH. Complex I was the most prominent protein that was persistently glutathionylated by GSSG in the presence of Grx2. Maintenance of complex I with an oxidized GSH/GSSG ratio led to a dramatic loss of activity, suggesting that oxidation of the mitochondrial glutathione pool may contribute to the selective complex I inactivation seen in Parkinson's disease. Most significantly, Grx2 catalyzed reversible protein glutathionylation/deglutathionylation over a wide range of GSH/GSSG ratios, from the reduced levels accessible under redox signaling to oxidized ratios only found under severe oxidative stress. Our findings indicate that Grx2 plays a central role in the response of mitochondria to both redox signals and oxidative stress by facilitating the interplay between the mitochondrial glutathione pool and protein thiols.Oxidative damage and redox signaling can regulate protein thiol redox state (1-4). A major way in which this occurs is through the response of protein thiols to changes in the glutathione (GSH) to glutathione disulfide (GSSG) ratio (2, 5, 6). The intracellular GSH/GSSG ratio is usually kept high (Ͼ99% reduced) through reduction of GSSG to GSH by glutathione reductase, enabling GSH to act as an antioxidant (2, 6). However, during oxidative stress or redox signaling reactive oxygen species (ROS) 1 oxidize GSH to GSSG directly, or catalyzed by glutathione peroxidases. Protein thiols respond to the decreased GSH/GSSG ratio by forming mixed disulfides with glutathione through thiol-disulfide exchange between the thiolate anion and GSSG (protein thiols typically have pK a values of ϳ8 -9, but these can vary widely depending on the local e...

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“…Complex I was markedly more susceptible to glutathionylation and irreversible inactivation than other respiratory chain complexes. This may explain why complex I is selectively damaged in Parkinson's disease or Huntington's disease (16,17,47) and indicates why mitochondrial oxidative stress and glutathione depletion are common features of these diseases (48,49). Redox active complex I thiols also reacted with S-nitroso compounds, probably by transnitrosation to form S-nitrosothiols.…”

Section: Formation Of Complex I Protein-glutathione Mixed Disulfides mentioning

confidence: 99%

Reversible Glutathionylation of Complex I Increases Mitochondrial Superoxide Formation

Taylor

Hurrell

Shannon

et al. 2003

Journal of Biological Chemistry

368

272

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Increased production of reactive oxygen species (ROS) by mitochondria is involved in oxidative damage to the organelle and in committing cells to apoptosis or senescence, but the mechanisms of this increase are unknown. Here we show that ROS production by mitochondrial complex I increases in response to oxidation of the mitochondrial glutathione pool. This correlates with thiols on the 51-and 75-kDa subunits of complex I forming mixed disulfides with glutathione. Glutathionylation of complex I increases superoxide production by the complex, and when the mixed disulfides are reduced, superoxide production returns to basal levels. Within intact mitochondria oxidation of the glutathione pool to glutathione disulfide also leads to glutathionylation of complex I, which correlates with increased superoxide formation. In this case, most of this superoxide is converted to hydrogen peroxide, which can then diffuse into the cytoplasm. This mechanism of reversible mitochondrial ROS production suggests how mitochondria might regulate redox signaling and shows how oxidation of the mitochondrial glutathione pool could contribute to the pathological changes that occur to mitochondria during oxidative stress.

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Glutathione in Parkinson's disease: A link between oxidative stress and mitochondrial damage?

Cited by 98 publications

References 27 publications

FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation

FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation

Glutaredoxin 2 Catalyzes the Reversible Oxidation and Glutathionylation of Mitochondrial Membrane Thiol Proteins

Reversible Glutathionylation of Complex I Increases Mitochondrial Superoxide Formation

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