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PROTEIN POST-TRANSLATIONAL MODIFICATIONS IN THE CELL’S REDOX
AND ENERGY STATES
by
Jerome Vincent Garcia
_____________________________________________________________________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR PHARMACOLOGY AND TOXICOLOGY)
May 2007
Copyright 2007 Jerome Vincent Garcia
Object Description
| Title | Protein post-translational modifications in the cell's redox and energy states |
| Author | Garcia, Jerome Vincent |
| Author email | jvg@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Pharmacology & Toxicology |
| School | School of Pharmacy |
| Date defended/completed | 2007-03-27 |
| Date submitted | 2007 |
| Restricted until | Unrestricted |
| Date published | 2007-05-03 |
| Advisor (committee chair) | Cadenas, Enrique |
| Advisor (committee member) |
Sevanian, Alex Alkana, Ronald Hsiai, Tzung |
| Abstract | The increased generation of reactive oxygen and nitrogen species and glutathione depletion creates profound changes in the redox status of the cell and has been implicated in the progression of neurodegenerative diseases such as Parkinson's disease. Redox regulation has become exceedingly important in understanding the cellular adaptation to oxidative stress. However, it remains unclear how changes in the cellular and mitochondrial redox environment affect redox sensitive protein function during exposure to NO and dopamine and the consequences of such changes with respect to mitochondrial function and redox signaling (achieved through post-translational modifications).; The work in this dissertation demonstrates that glutathionylation of mitochondrial proteins occurs during oxidative stress. This modification functions as a store of GSH and is released in response to changes in mitochondrial redox and energy status. Protein sulfhydryl recovery (de-glutathionylation) of mitochondrial proteins in energized mitochondria increased the GSH buffering capacity of mitochondria against physiological and non-physiological concentrations of hydrogen peroxide (H2O2), thus preventing drastic changes in mitochondrial redox status. This is exemplified using a Parkinson's disease model with NO and dopamine as modifiers of the redox environment. The reaction between NO and dopamine oxidation produces ONOO-, a powerful oxidant that leads to a 72% inhibition of mitochondrial respiration in isolated mitochondria and 71% inhibition in PC12 cells.; Additionally, we identified aconitase and ATP synthase as targets of protein post-translational modifications. Nitration of aconitase by ONOO- resulted in a dose-dependent decrease in aconitase function. In the presence of citrate, a substrate for aconitase, a 66-fold higher concentration of ONOO- was required for half-maximal inhibition. Glutathionylation of aconitase and ATP synthase also resulted in an inhibition of enzyme function. De-glutathionylation of ATP synthase resulted in a 221% change in activity. It is well established that damage to proteins under conditions of oxidative and nitrosative stress is highly specific, and plays an important role in many diseases. Characterization of post-translational modifications of mitochondrial proteins provides a mechanism for .NO and dopamine elicited damage to mitochondrial function leading to apoptosis of dopaminergic neurons in Parkinson's disease. |
| Keyword | mitochondria; redox; protein post-translational modifications |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m480 |
| Rights | Garcia, Jerome Vincent |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Garcia-20070503 |
| Archival file | uscthesesreloadpub_Volume40/etd-Garcia-20070503.pdf |
Description
| Title | Page 1 |
| Full text | PROTEIN POST-TRANSLATIONAL MODIFICATIONS IN THE CELL’S REDOX AND ENERGY STATES by Jerome Vincent Garcia _____________________________________________________________________ A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR PHARMACOLOGY AND TOXICOLOGY) May 2007 Copyright 2007 Jerome Vincent Garcia |
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