Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.786166
Title: Detecting mitophagy in mitochondrial disease : towards a new type of therapy
Author: Dombi, Eszter
ISNI:       0000 0004 7971 6334
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Abstract:
Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins. Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of disorders that can present at any age and can affect any type of tissue. The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional and redundant mitochondria through a specific quality control mechanism termed mitophagy. Mitochondria could be targeted for autophagic degradation for a variety of reasons including basal turnover for recycling, starvation induced degradation, and degradation due to damage. While the core autophagic machinery is highly conserved and common to most pathways, the signalling pathways leading to the selective degradation of damaged mitochondria are still not completely understood. The aim of this thesis is to investigate mitophagy in several mitochondrial disease. Additionally, to test potential drug modulators of mitophagy with the view that they may provide an alternative therapy for certain kinds of mitochondrial diseases in the future. Twenty-nine patient derived fibroblast lines were investigated. Most patient cells had dysregulated mitophagy, where mitochondrial turnover was often higher when compared to control cell lines. Amongst the potential drug modulators, Metformin, AICAR, Chlorodiazepoxide, and Duloxetine were sufficient at inducing mitophagy without a cytotoxic effect. Altered mitophagy seems to be a hallmark of many mitochondrial diseases and the trigger might be crucial to the phenotype, therefore it offers a potential therapeutic target. Identifying potential drug modulators of mitophagy is the first step towards a novel therapy for not only mitochondrial disease but many neurodegenerative disorders as well. Monitoring mitophagy could also be useful for assessing the efficacy of certain treatments or even supplements on an individual level, as the effect of drugs that benefit patients can manifest in alleviation of the increased mitochondrial turnover.
Supervisor: Poulton, Joanna ; Churchill, Grant Sponsor: Lily Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.786166  DOI: Not available
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