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C-JUN N-TERMINAL KINASE (JNK) MEDIATED INHIBITION OF
PYRUVATE DEHYDROGENASE (PDH) ACTIVITY AND ITS EFFECT ON
MITOCHONDRIAL METABOLISM DURING BRAIN AGING
by
Qiongqiong Zhou
______________________________________________________________
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)
December 2006
Copyright 2006 Qiongqiong Zhou
Object Description
| Title | C-jun N-terminal Kinase (JNK) mediated inhibition of Pyruvate Dehydrogenase (PDH) activity and its effect on mitochondrial metabolism during brain aging |
| Author | Zhou, Qiongqiong |
| Author email | qiongqiz@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Pharmacology & Toxicology |
| School | School of Pharmacy |
| Date defended/completed | 2006-10-05 |
| Date submitted | 2006 |
| Restricted until | Unrestricted |
| Date published | 2006-11-14 |
| Advisor (committee chair) | Cadenas, Enrique |
| Advisor (committee member) |
Brinton, Roberta Hsiai, Tzung |
| Abstract | Mitochondrial dysfunction has often been found to occur in brains with advancing age or neurodegerative diseases. Recent work demonstrated that upon activation, JNK translocates to mitochondria and regulates mitochondrial functions in cultured cells. Using experimental models of cultured primary neurons and isolated brain mitochondria, we found that: (i) both anisomycin, a potent JNK activator, and hydrogen peroxide can induce the rapid activation of JNK and its translocation to mitochondria in cultured primary cortical neurons, (ii) mitochondria-associated active JNK can be degraded by Proteinase K, which indicates that active JNK associates with the outer membrane of mitochondria, and (iii) the association of active JNK with mitochondria causes an increase of pyruvate dehydrogenase (PDH) phosphorylation and inhibition of its activity, which results in an increase of lactic acid concentration and decrease of ATP level in the cells. These results indicate that active JNK might mediate communication between the cytosol and mitochondria, regulating mitochondrial metabolism according to the cytosolic environment. Using an aged rat model, we found that: (i) JNK activity and its translocation to mitochondria were increased in the brain during aging, whereas PDH activity was diminished, with increased phosphorylation of the PDH E1[alpha]; subunit with age in rat brains, and (ii) both ATP levels and GSH/GSSG ratios tended to decrease during aging, whereas concentrations of lactic acid were significantly increased. These results indicate that PDH inhibition mediated insufficiency of energy production and the availability of reducing molecules (GSH), that acidosis may play an important role in brain aging, and that the inhibition of PDH may be mediated by increased translocation of JNK to mitochondria during aging. The studies acquire further significance, because mitochondrial metabolic activity is critical to nervous system function.; An abnormally high level of JNK activity in the brain may cause severe inhibition of PDH, whichmay contribute to the development of the pathological stages of many neurodegenerative diseases. |
| Keyword | neurodegeneration JNK mitochondria aging |
| 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-m133 |
| Rights | Zhou, Qiongqiong |
| 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-Zhou-20061114 |
| Archival file | uscthesesreloadpub_Volume23/etd-Zhou-20061114.pdf |
Description
| Title | Page 1 |
| Full text | C-JUN N-TERMINAL KINASE (JNK) MEDIATED INHIBITION OF PYRUVATE DEHYDROGENASE (PDH) ACTIVITY AND ITS EFFECT ON MITOCHONDRIAL METABOLISM DURING BRAIN AGING by Qiongqiong Zhou ______________________________________________________________ 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) December 2006 Copyright 2006 Qiongqiong Zhou |
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