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Mitophagy and Mitochondrial DNA Disease

King, Louise; (2018) Mitophagy and Mitochondrial DNA Disease. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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This thesis focuses on the mechanism of mitophagy and the initiation of mitophagy in various cell models derived from patients harbouring pathogenic mutations in the mitochondrial genome. Mitochondrial DNA mutations are maternally inherited and present with considerable clinical heterogeneity. Pathogenic cases can be homoplasmic or heteroplasmic; the latter of which means that wild- type and mutant mitochondria coexist. Particularly in cases of heteroplasmy, it is unclear how critical levels of mutant load can be reached, despite the presence of mitochondrial quality control pathways such as mitophagy. Mitophagy is a quality control process which facilitates the complete elimination of dysfunctional mitochondria. Mitophagy is known to be stimulated by a loss of mitochondrial membrane potential, however other triggers of the process are well less characterised. Here, the compound Rhodamine 6G was used to demonstrate the triggering of mitophagy independently of membrane potential in a Parkin-overexpressing neuroblastoma cell line model. Further analysis suggested that this compound generates mild oxidative stress and deep-sequencing of mitochondrial genome revealed the presence of mtDNA mutations upon exposure to Rhodamine 6G. The role of mitophagy in primary mitochondrial DNA disease is poorly understood. Using several patient fibroblast lines containing different mutations, significant impairments were identified in the ubiquitination of mitofusins upon stimulation of the mitophagy pathway and a considerable activation of mitochondrial biogenesis was observed, which did not occur in control fibroblasts. Further 5 experiments were performed focusing on the m.7472insC mutation, in which similarities in morphology and function were identified between these and PINK1 mutant fibroblasts. The m.7472insC fibroblasts were reprogrammed to induced pluripotent stem cells and differentiated to cortical neurons and myoblasts. Using a mitochondrial uncoupler, significant reductions in the accumulation of PINK1 and degradation of mitofusin 1 were observed in mutant myoblasts, however this was not seen in the mutant neurons.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Mitophagy and Mitochondrial DNA Disease
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: https://discovery.ucl.ac.uk/id/eprint/10043560
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