Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.747608
Title: Manipulating the segregation of human mitochondrial DNA
Author: Mennuni, M.
ISNI:       0000 0004 7231 8165
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Abstract:
Mitochondria contain their own DNA (mtDNA), which is tiny compared to the nuclear genome and it is present in thousands of copies in the cell. This feature can lead to the coexistence of different variants within the same cell or individual, a phenomenon known as heteroplasmy and a key characteristic of many mitochondrial disorders. Typically, these diseases manifest only when the mutant mtDNAs substantially outnumber the normal copies. Therefore, even a small increase in the proportion of wild-type mtDNA can markedly improve mitochondrial function. The level of mutant mtDNA is known to be influenced by the nuclear genome, but the exact mechanism underlying the selection is still obscure. The study of the unique behaviour of A549 cells in preferring the wild-type mtDNA has led to the identification of pathways potentially important for the selection of normal mtDNA molecules. This led to the identification of a small molecule able to decrease the mutant mtDNA in heteroplasmic cells and to significantly improve mitochondrial function. After the efficacy of the compound was proved in cybrid and fibroblast cellular models, the pathways and processes affected by the compound were investigated. Both boosting the respiratory chain (RC) function and inducing ER stress appear to be necessary for the selection, but neither alone has proven to be sufficient. Moreover, the enhancement of mitochondrial function was associated with the expression of p62. The compound’s dual action of enhancing mitochondrial RC and inducing survival by activating the ER stress response, seems to be determinant in exerting a selective pressure and allow the discrimination between functional and dysfunctional mitochondria. Ultimately, the selection results from a fine tuning of selective removal of defective mitochondria by mitophagy and selective propagation of wild-type mtDNA molecules.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.747608  DOI: Not available
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