Abnormal regulation of mitochondrial deoxyribonucleoside triphosphate pools can lead to mitochondrial DNA depletion syndromes, a set of genetic diseases associated with depletion of mitochondrial DNA. Besides mitochondrial DNA depletion syndromes, improper maintenance of mitochondrial deoxyribonucleoside triphosphate pools and mitochondrial DNA have also been implicated in a host of other human pathologies. The unifying objective of this dissertation was to enhance our knowledge of the regulation of mitochondrial deoxyribonucleoside triphosphate pools. The first step was to investigate the characteristics of mitochondrial and cytoplasmic deoxyribonucleoside triphosphate levels. I calculated mitochondrial and cytoplasmic deoxyribonucleoside triphosphate concentrations from previously published data. Cytoplasmic and mitochondrial deoxyribonucleoside triphosphates are strongly correlated in normal cells but not in transformed cells. Following up this discovery with analysis of gene expression, I discovered that, consistent with the trends in deoxyribonucleoside triphosphate concentrations in cells, genes coding for enzymes that maintain cytoplasmic and mitochondrial deoxyribonucleoside triphosphates have correlated expression across normal tissues but not across transformed tissues. To further understand the influence of cytoplasmic deoxyribonucleoside triphosphates on mitochondrial deoxyribonucleoside triphosphates, I simulated the metabolism of mitochondrial deoxyribonucleosides with a computational model. Cytoplasmic deoxyribonucleotides have a substantial and indispensable contribution to mitochondrial deoxyribonucleoside triphosphates in most circumstances. My results further show that import from the cytoplasm would need to occur at either deoxyribonucleoside diphosphate or triphosphate levels.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11292011-142606 |
| Date | 01 December 2011 |
| Creators | Gandhi, Vishal V |
| Contributors | Tricia Thornton-Wells, Emmanuele DiBenedetto, David Samuels, Scott Williams, Todd Hulgan |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-11292011-142606/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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