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Funded Studies

Functional Consequences of Glutathione-Mixed Disulfide Formation in Brain Mitochondria

Glutathione depletion and mitochondrial defects have been implicated in the etiology of Parkinson's disease (PD). Our previous work examined the cellular mechanisms underlying dopamine cell loss in vitro and in vivo due to impairment of energy metabolism. We found that glutathione (GSH) plays a pivotal role in the susceptibility of dopamine neurons to disturbances in energy metabolism. This has lead to a new area of investigation to understand the various contributions made by GSH in survival of dopamine neurons. One role played by GSH, which has received little attention, is in GSH-mixed disulfide formation. Increased oxidative stress can result in an increase in GSH-mixed disulfide formation in the cell and subcellular organelles such as mitochondria. This formation is postulated to serve both physiological and pathophsiological roles. Virtually nothing is known regarding the consequences of GSH-mixed disulfide formation on mitochondrial enzyme activities or if mitochondria contain the enzyme to dethiolate and remove GSH, i.e., thioltransferase. The following study will test the hypothesis that GSH-mixed disulfide formation alters activity of some Krebs cycle and electron transport chain enzymes. We will also determine if brain mitochondria contain thioltransferase. These studies will provide important, novel information regarding the functional consequences of protein-glutathione-mixed disulfide formation in mitochondria and whether mitochondria contain thioltransferase activity needed to reverse mixed disulfide formation. Given the finding of a reduced amount of glutathione and mitochondrial defects in the sporadic PD population, information about this little studied role of glutathione and its associated enzyme in mitochondria may provide new insights in our understanding of the cellular mechanisms underlying DA cell damage in PD.


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