Mitchell, ALR;
(2018)
The Mitochondrial Response to Nutrient Availability in Cancer Cells and Cellular Models of Mitochondrial Diseases.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Mitochondria are central to cellular metabolism; therefore, changes in nutrient availability are expected to impact the organelle’s function. To assess the interdependence of mitochondria and nutrients, two models were investigated: rapidly proliferating cells, and fibroblasts derived from patients with mitochondrial disorders. In Human Embryonic Kidney (HEK) cells, amino acid withdrawal increases mitochondrial function (Johnson et al., 2014). Investigation of two unrelated cell lines, A549 and HeLa cells, revealed perturbed regulation of cytosolic translation, and reduced mitochondrial function during amino acid starvation. This was associated with reduced survival compared to HEK cells, demonstrating that these cells differ in their nutrient-processing pathways in response to amino acid deprivation. Assessment of mitochondrial protein translocases for a role in retrograde signalling revealed that Tim17A, a component of the TIM23 translocase, is rapidly downregulated during amino acid withdrawal, in all cell lines investigated. Among the amino acids, cysteine metabolism has previously been suggested to be important for the spontaneous recovery from certain mitochondrial translation disorders (Boczonadi et al., 2013; Zeharia et al., 2009). Investigation into the regulation of the transsulphuration pathway (TSP), which produces cysteine as well as catabolising it to hydrogen sulphide (H2S), revealed interindividual differences in TSP expression in fibroblasts with a mutation in mitochondrial tRNA modifying enzymes. Strikingly, one patient surviving to adulthood in a normally fatal infantile disease showed upregulation of H2S-detoxifying enzyme, SQR, and its catabolite, thiosulphate. Furthermore, the TSP and SQR were induced using a pharmacological model of mitochondrial dysfunction, highlighting the response of this pathway to mitochondrial disease. Together, these data demonstrate the central role of the mitochondria in nutrient metabolism and stress response, and the possibility to adapt metabolic pathways to ameliorate the pathological consequences of mitochondrial defects.
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