Duberley, KE; (2013) Neurometabolic Implications of Coenzyme Q10 Deficiency: Pathogenesis, Detection and Treatment. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Disorders of Coenzyme Q10 (CoQ10) biosynthesis represent the most treatable subgroup of mitochondrial diseases. Neurological involvement is frequently observed in CoQ10 deficiency, typically presenting as cerebellar ataxia and/or seizures. The aetiology of the neurological presentation of CoQ10 deficiency has yet to be fully elucidated and therefore in order to investigate these phenomena we have established a neuronal cell model of CoQ10 deficiency by treatment of the neuronal SH-SY5Y cell line with Para-AminoBenzoic Acid (PABA). This neuronal cell model provides insights into the effects of CoQ10 deficiency on neuronal mitochondrial function and oxidative stress. A marginal decrease in CoQ10 status (76% residual CoQ10) appears to be sufficient to impair Electron Transport Chain (ETC) function and increase mitochondrial oxidative stress, highlighting the vulnerability of neurons to a small deficit in CoQ10 status. In contrast to CoQ10 deficient fibroblasts, a CoQ10 deficiency (46% residual CoQ10) in neuronal cells appears to result in reversal of Complex V activity. This phenomenon has not been reported in previous studies of CoQ10 deficiency and may be a unique characteristic of neuronal cells. This neuronal cell model was subsequently utilised in the evaluation of candidate therapies for neurological conditions associated with CoQ10 deficiency. The efficacy of CoQ10 supplementation and methylene blue (MB) treatment were evaluated. CoQ10 supplementation proved effective at preventing mitochondrial oxidative stress and partially restoring neuronal mitochondrial function. However ETC complex activities were still compromised, suggesting an explanation for the refractory nature of neurological CoQ10 deficiency to treatment. Muscle is considered the “gold standard” for CoQ10 quantification; however neurological CoQ10 deficiency does not always present with a significant decrease in muscle CoQ10 status, despite a genetic diagnosis of CoQ10 deficiency. Cerebrospinal Fluid (CSF) CoQ10 quantification offers a more direct measurement of cerebellar CoQ10 levels. A tandem mass spectrometry (MS/MS) method capable of quantifying nanomolar (nM) levels of CoQ10 was therefore developed. In conclusion this PhD thesis has been successful in expanding our understanding of the pathophysiology of neuronal CoQ10 deficiency and subsequently suggesting why neurological CoQ10 deficiency might be refractory to CoQ10 treatment. This thesis has also led to the development of a new technique for quantification of CSF CoQ10 concentration, opening up many possibilities for future studies and applications. This project is funded by Ataxia UK (www.ataxiauk.org.uk).

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