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Title: Investigation of mitochondrial m.1555A > G aminoglycoside hearing loss
Author: O'Sullivan, M. E.
ISNI:       0000 0004 8502 0931
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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The mitochondrial DNA mutation, m.1555A > G, predisposes to severe hearing loss following aminoglycoside antibiotic exposure. The m.1555A > G mutation can also lead to hearing loss in the absence of antibiotic exposure termed non-syndromic m.1555A > G hearing loss. Two distinct concepts of mitochondrial dysfunction related to the m.1555A > G mutation have been postulated - mRNA misreading and 12S m⁶₂A rRNA methylation. Evidence from cell and animal models has indicated that m.1555A > G may make the 12S rRNA a better substrate for m⁶₂A methylation by the mitochondrial transcription factor B1 (TFB1M) enzyme, resulting in a higher ratio of methylated: unmethylated 12S rRNA transcripts in the mitochondrion, so called 'hypermethylation'. Hypermethylation is thought to trigger a cascade of events, which results in mitochondrial dysfunction and hearing loss. Using a novel fluorescent method, suitable for paediatric patients, 12S m⁶₂A rRNA methylation was investigated in primary and non-primary cell-derived RNA samples from patients with m.1555A > G and controls. The data presented in this work indicates that previous findings may be an artefact of the experimental models used to study this hypothesis and 12S m⁶₂A rRNA methylation is unlikely to be a pathogenic mechanism. Aminoglycoside-induced reactive oxygen species (ROS) production is reported to play a key role in cochlear cell death. It is hypothesised that increased mitochondrial mRNA misreading disrupts oxidative phosphorylation, which leads to increased ROS. Using a multiplex flow cytometry-based method to measure mitochondrial superoxide, the response of cells from cases with m.1555A > G and controls to aminoglycoside treatment was examined. The data indicates that the control response to aminoglycoside treatment is variable. Exploring this variation will be crucial if the effects of antibiotic-induced changes in mitochondrial mRNA misreading are to be investigated and the cellular events that ensue to be targeted for treatment.
Supervisor: Bitner-Glindzicz, M. ; Rahman, S. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available