Autosomal dominant optic atrophy (ADOA) is a mitochondrial disorder caused by a nuclear DNA mutation. The mutation is within the OPA1 gene, which encodes a 120kDa protein product. The protein, OPA1, is a dynamin like GTPase, which is responsible for fusion of mitochondria. It is located in the inner mitochondrial membrane and functions in conjunction with outer membrane fission proteins to maintain mitochondrial integrity. The OPA1 protein is expressed ubiquitously and heterozygous mutations cause atrophy of the optic nerve. The variability in human ADOA phenotype may suggest some level of susceptibility to vision loss whereas other individuals appear symptom free. The Opa1 Q285STOP mouse model of ADOA provides a unique opportunity to examine the disease pathology with respect to mitochondrial haploinsufficiency. The tissue specificity of the disease suggests local control over the OXPHOS environment. The bioenergetic activity of Opa1Q285STOP mouse is currently unestablished. The status of antioxidant activity supporting bioenergetic function may be vital in maintaining stability within fusion deficient mitochondria. Mitochondrial stability could influence the extent of reactive species, and ultimately, ATP production. This thesis combined the study of mitochondrial haploinsufficiency with analysis of OXPHOS and antioxidant levels in Opa1Q285STOP mouse where a bioenergetic deficit was identified in all mitochondria tested. The addition of a plant derived antioxidant and its potential effects within the retinal environment and surrounding central nervous system of Opa1 Q285STOP mouse did not appear to influence the extended phenotypic profile observed in this mouse model. The administration of resveratrol to the wild type population conferred disadvantages both In Vivo and In Vitro.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:649443 |
| Date | January 2015 |
| Creators | Waters, Caroline |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/73770/ |
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