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dc.contributor.authorStout, Roisin Bridget-
dc.descriptionPhD Thesisen_US
dc.description.abstractMitochondrial dysfunction is found in ageing tissues and has been specifically implicated in the progression of extrinsic ageing in skin through a cycle of oxidative stress and dysfunction. Primary mitochondrial disease (PMD) is caused by genetic abnormalities that effect mitochondrial oxidative phosphorylation and patients may present prematurely with agerelated disorders such as dementia, sensorineural hearing loss, and muscle weakness. This thesis aims to explore the link between chronic and extrinsic ageing, and mitochondrial dysfunction using primary mitochondrial disease as a model. HDFn cells are commonly cultured in high glucose media supplemented with 10% FBS, which ensures continuous growth. However, the level of glucose is not physiologically relevant. Cells in this media; a glucose free media to induce mitochondrial energy production; and a 2% FBS supplementation to reduce cell growth, were stressed with solar light to determine the effect of dose and culture condition on response to solar light irradiation. High glucose DMEM supplemented with 10% FBS had reduced mtDNA repair in response to solar stress and increase mitochondrial ROS, therefore this culture condition could artificially increase the damage response. Chronic repeated doses of solar light, as opposed to single acute doses, had an accumulative increase of mtDNA damage and resulted in reduced oxidative damage post solar stress, thereby having a protective effect against subsequent doses. After solar stress, fibroblasts reduced the majority of mtDNA damage between 8 and 24 hours, and mtDNA network returns to control levels within 8 hours. Overall, culture conditions affect mitochondrial damage response from solar stress and highly proliferative cells grown in high glucose media may not reflect a physiological environment. Low glucose media provides a physiologically relevant alternative to high glucose media, and further investigation into appropriate addition of growth serum would be beneficial to optimise solar stress studies. This study also optimised the appropriate times to study mtDNA damage and mitochondrial network response to solar light damage in dermal fibroblasts cells. Premature facial ageing and clinical facial features were assessed in PMD patients by systematic review of case reports and cohort studies; a pilot study was conducted in adult PMD patients to assess facial ageing using human evaluators and a convolution neural network. Results from the systematic review found ocular manifestations of mitochondrial disease include ptosis (eyelid drooping) and ophthalmoplegia (restricted eye movement) that are predominately found in patients with mtDNA deletions in the mitochondrial genome, and highest in patients with single large-scale deletions. However, the overall facial appearance in ii patients is underreported and under-investigated. Ptosis in patients may be linked to increased perceived age, though patients on average had reduced levels of sun damage in the form of UV spots. This patient study found there could be a confounding effect between skin appearance and overall facial structure when assessing perceived age between the PMD patient cohort and controls. Notably, no previous literature existed on premature ageing in PMD. Ptosis could be a substantial contributor to overall perceived age and future expansion of the study would benefit from interrogating a larger cohort of patients harbouring large-scale single and multiple mtDNA deletions.en_US
dc.description.sponsorshipNIHR: National Institute for Health and Care Researchen_US
dc.publisherNewcastle Universityen_US
dc.titleInterrogating mitochondrial dysfunction in facial appearance and ageingen_US
Appears in Collections:Translational and Clinical Research Institute

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