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TARGETS OF PROTEIN NITRATION IN MITOCHONDRIA DURING AGING
by
Catherine Brégère
________________________________________________________________________
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 2008
Copyright 2008 Catherine Brégère
Object Description
| Title | Targets of protein nitration during aging |
| Author | Brégère, Catherine |
| Author email | bregere@hotmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Pharmacology & Toxicology |
| School | School of Pharmacy |
| Date defended/completed | 2007-11-16 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-02-04 |
| Advisor (committee chair) | Sohal, Rajindar S. |
| Advisor (committee member) |
Shen, Wei-Chiang Shih, Jean C. Kaplowitz, Neil |
| Abstract | The main goal of this study was to test the hypothesis that specific proteins undergo an age-related increase in nitration, which results in their functional alteration, and that calorie restriction (CR), a regimen which prolongs the life span of many rodents, can attenuate or postpone such age-associated changes. Succinyl-CoA transferase (SCOT) and enoyl-CoA hydratase (ECH), two enzymes involved in energy production, were detected immunochemically with an anti-3-nitrotyrosine antibody to be targets of nitration in mitochondria from Fischer rat tissues. Mass spectrometric studies revealed that, rather than tyrosine, tryptophan 372, located in the vicinity of key catalytic residues, was the site of a novel posttranslational modification, namely nitrohydroxytryptophan in the SCOT protein. This amino acid alteration was also detected in mice, pig and cow, but not rabbit, suggesting that oxidative/nitrative mechanisms targeting this particular tryptophan residue are relatively well conserved, but not universal, among mammals. In rat heart mitochondria, an increase in nitrohydroxytryptophan content was associated with an elevation in SCOT specific catalytic activity during aging, while SCOT protein amounts remained unchanged.; In contrast to heart, the amounts of SCOT protein declined significantly with age in kidney, whereas the nitration and specific activity remained unchanged. CR selectively attenuated the age-related changes in the amount of SCOT protein in kidney mitochondria, but had no effect in the heart. Both in vivo and in vitro data indicated that nitration/oxidation of tryptophan may activate the SCOT protein in rat heart during aging. Nitrated SCOT was relatively more susceptible to undergo in vitro proteolysis than the unmodified enzyme. In C57BL/6 and DBA/2 mice, SCOT protein amount, degree of its nitration and catalytic activity remained unaffected with age. CR induced a similar quantitative decrease in the content of SCOT protein in both strains. Overall, SCOT catalytic activity seemed to be modulated by its degree of nitration and the amounts of protein. Age and CRrelated changes in ECH catalytic activity appeared to be mostly correlated with levels of ECH protein. In general, the results imply that there is a shift in the utilization of ketone bodies during aging in Fischer rats, but not in C57BL/6 and DBA/2 mice. The degree of SCOT nitration remained unaffected by CR, suggesting that the CR effect does not involve SCOT. The impact of age and CR were tissue and species specific. |
| Keyword | aging; mitochondria; nitration |
| 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-m1006 |
| Rights | Brégère, Catherine |
| 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-bregere-20080204 |
| Archival file | uscthesesreloadpub_Volume32/etd-bregere-20080204.pdf |
Description
| Title | Page 1 |
| Full text | TARGETS OF PROTEIN NITRATION IN MITOCHONDRIA DURING AGING by Catherine Brégère ________________________________________________________________________ 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 2008 Copyright 2008 Catherine Brégère |
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