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Subcellular Glutathione Distribution...

Darch, Maxwell Austin.

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Subcellular Glutathione Distribution During Severe Redox Stress and Characterizing Thiol Redox Control of Human Cu, Zn Superoxide Dismutase.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Subcellular Glutathione Distribution During Severe Redox Stress and Characterizing Thiol Redox Control of Human Cu, Zn Superoxide Dismutase./
作者:	Darch, Maxwell Austin.
面頁冊數:	152 p.
附註:	Source: Dissertation Abstracts International, Volume: 76-10(E), Section: B.
Contained By:	Dissertation Abstracts International76-10B(E).
標題:	Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3704318
ISBN:	9781321766349

Subcellular Glutathione Distribution During Severe Redox Stress and Characterizing Thiol Redox Control of Human Cu, Zn Superoxide Dismutase.
Darch, Maxwell Austin.

Subcellular Glutathione Distribution During Severe Redox Stress and Characterizing Thiol Redox Control of Human Cu, Zn Superoxide Dismutase. - 152 p.

Source: Dissertation Abstracts International, Volume: 76-10(E), Section: B.

Thesis (Ph.D.)--University of South Carolina, 2015.

Intracellular thiol-disulfide balance within eukaryotic cells is critical for maintaining proper cellular function. Redox imbalance can result in mitochondrial dysfunction, which is linked to several neurodegenerative diseases and the overall aging process. A ubiquitous tripeptide, glutathione (GSH), plays an important role in detoxifying reactive oxygen species (ROS), carcinogens, and in the control of cancer-related genes. The main source and target of ROS is the mitochondrion, therefore understanding of redox equilibrium in this compartment is of critical interest. GFP-based sensors targeted to the intermembrane space (IMS) and matrix of yeast mitochondria were developed in our lab to characterize compartments individually. Our previous studies using these sensors have shown that the IMS is more oxidizing than the cytosol and matrix, and redox control is maintained separately in subcellular compartments. Current studies are aimed to elucidate the effects of GSH overaccumulation on redox balance as well as pathways for GSH:GSSG subcellular compartmental exchange using Saccharomyces cerevisiae as a model system. To examine the effects of extreme redox imbalance, a yeast strain that overaccumulates GSH was studied in conjunction with GFP-based cytosolic, IMS and matrix redox sensors. GSH and GSSG overaccumulation were found to directly impact GSH:GSSG pools and thiol redox pathways in the IMS, while having little effect on the matrix. To further elucidate GSH:GSSG exchange between subcellular compartments and identify sources of GSSG production, several gene knockout strains were used to impair redox defense mechanisms at the cellular and subcellular level. Overall, these studies provide evidence for specific exchange of GSH and GSSG between the IMS and cytosol under redox stress.

ISBN: 9781321766349Subjects--Topical Terms:

518028
Biochemistry.

Subcellular Glutathione Distribution During Severe Redox Stress and Characterizing Thiol Redox Control of Human Cu, Zn Superoxide Dismutase.
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245 1 0 $a Subcellular Glutathione Distribution During Severe Redox Stress and Characterizing Thiol Redox Control of Human Cu, Zn Superoxide Dismutase.
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500 $a Source: Dissertation Abstracts International, Volume: 76-10(E), Section: B.
500 $a Advisers: Caryn E. Outten; John Dawson.
502 $a Thesis (Ph.D.)--University of South Carolina, 2015.
520 $a Intracellular thiol-disulfide balance within eukaryotic cells is critical for maintaining proper cellular function. Redox imbalance can result in mitochondrial dysfunction, which is linked to several neurodegenerative diseases and the overall aging process. A ubiquitous tripeptide, glutathione (GSH), plays an important role in detoxifying reactive oxygen species (ROS), carcinogens, and in the control of cancer-related genes. The main source and target of ROS is the mitochondrion, therefore understanding of redox equilibrium in this compartment is of critical interest. GFP-based sensors targeted to the intermembrane space (IMS) and matrix of yeast mitochondria were developed in our lab to characterize compartments individually. Our previous studies using these sensors have shown that the IMS is more oxidizing than the cytosol and matrix, and redox control is maintained separately in subcellular compartments. Current studies are aimed to elucidate the effects of GSH overaccumulation on redox balance as well as pathways for GSH:GSSG subcellular compartmental exchange using Saccharomyces cerevisiae as a model system. To examine the effects of extreme redox imbalance, a yeast strain that overaccumulates GSH was studied in conjunction with GFP-based cytosolic, IMS and matrix redox sensors. GSH and GSSG overaccumulation were found to directly impact GSH:GSSG pools and thiol redox pathways in the IMS, while having little effect on the matrix. To further elucidate GSH:GSSG exchange between subcellular compartments and identify sources of GSSG production, several gene knockout strains were used to impair redox defense mechanisms at the cellular and subcellular level. Overall, these studies provide evidence for specific exchange of GSH and GSSG between the IMS and cytosol under redox stress.
520 $a An additional cellular antioxidant is superoxide dismutase 1 (SOD1), which catalyzes the dismutation of the radical superoxide to oxygen and hydrogen peroxide. Nascent SOD1 polypeptides undergo metal insertion and disulfide bond formation to reach the mature active form. Mutations in hSOD1 have been causally linked to the familial form of amyotrophic lateral sclerosis (ALS), a common neurodegenerative disease. The molecular mechanism for SOD1-linked ALS pathology remains elusive; however, previous results demonstrate that ALS human superoxide dismutase 1 (hSOD1) mutants exhibit greater susceptibility to disulfide reduction, unfolding/misfolding, and metal loss, which leads to protein aggregation. Our goal was to determine which factors play a role in disulfide redox control of this enzyme by probing the interaction between hSOD1, GSH and glutaredoxins. We demonstrate that human glutaredoxin 1 (hGrx1) uses a monothiol mechanism to reduce the hSOD1 disulfide, and the GSH/hGrx1 system reduces ALS mutant SOD1 at a faster rate than WT hSOD1. Overall, our studies suggest that differences in the GSH/hGrx1 reaction rate with WT vs. ALS mutant hSOD1 may contribute to the greater pathogenicity of ALS mutant hSOD1.
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