Proteins of the Bcl-2 family mediate apoptosis by altering mitochondrial structure, function, and integrity. However, in certain contexts, some members of the Bcl-2 family have additional, non-apoptotic functions. Bid, a BH3-only Bcl-2 family member, is a potent activator of mitochondrial apoptosis. However, Bid also preserves cell viability in conditions of replication stress by localizing to sites of DNA damage on the chromatin to facilitate signaling through the DNA damage response pathway. Using Bid deficient mice and cell lines, we investigated how the DNA damage response regulates the phosphorylation and subcellular trafficking of Bid. We demonstrate that Bid is shuttled between the nucleus and mitochondria in a time dependent manner following replication stress and that this shuttling is regulated by Crm1. We also provide evidence that chromatin localized Bid is phosphorylated. These data suggest that the DNA damage response influences the sub-cellular localization of Bid and that the phosphorylation of Bid may regulate its association with the chromatin. In addition, we explored additional, non-apoptotic functions of Bid on mitochondrial structure and physiology. Our findings indicate that Bid is essential for the maintenance of mitochondrial cristae structure, efficient respiration, cardiolipin composition, and cell viability in a manner that is independent of its apoptotic function. Furthermore, we show that Bid deficiency sensitizes mice to left ventricular cardiac dysfunction in conditions of increased cardiac stress. We also identify a significant association between BID SNPs and myocardial infarction in human patients. We also demonstrate that mitochondrial respiration is dependent on methionine 148 of Bid, a site that is mutated by one of the identified human Bid SNPs. Thus, Bid is essential for normal mitochondrial structure and physiology as well as for tolerance of the heart to acute stress.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-10062015-120253 |
| Date | 06 October 2015 |
| Creators | Bertram, Clinton Cody |
| Contributors | Sandra S Zinkel, James G. Patton, Matthew Tyska, William P. Tansey |
| 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-10062015-120253/ |
| 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. |
Page generated in 0.0018 seconds