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Title: Mechanisms of cellular metabolic regulation in short-term hypoxia
Author: Grimm, Fiona
ISNI:       0000 0004 7229 1169
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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In tumours, cell proliferation and inefficient perfusion lead to transient and chronic fluctuations of oxygen supply, causing localised hypoxia. A key mechanism for survival in hypoxia is the reprogramming of cellular metabolism, which current evidence suggests is primarily mediated at the transcriptional level by HIF1α. This work demonstrates that well-known, hypoxia-associated metabolic changes, such as increased glycolysis and lactate production, occur within only 3-5 hours at 1% O2 in a HIF1α-independent manner. Concomitant to these changes, intracellular aspartate levels decline, partly through decreased mitochondrial aspartate production, implying altered activity of the mitochondrial malate-aspartate shuttle (MAS). Pharmacological and genetic ablation experiments demonstrated that aspartate aminotransferase 1 (GOT1), a component of the MAS, is necessary for upregulation of glycolysis in early hypoxia. Loss of GOT1 also limited flux through cytoplasmic redox pathways and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and decreased the cytoplasmic NAD+/NADH ratio, suggesting that multiple redox systems collectively account for early hypoxia-induced metabolic changes. Furthermore, lactate dehydrogenase (LDHA) loss of function had a strong inhibitory effect on glycolytic flux, caused increased respiration and dependency on OXPHOS-derived ATP, and diversion of glucose carbons into the TCA cycle and fatty acid biosynthesis. In early hypoxia, LDHA knockout cells exhibited ATP depletion and AMPK activation and proliferation was inhibited irreversibly, indicating an important function of LDHA in maintaining ATP levels and regulating glucose carbon fate to ensure cell survival. In summary, this work reveals that key features of the cellular metabolic response to hypoxia are established early, prior to the onset of protein expression changes. These changes are orchestrated by a nexus of redox pathways to maintain cellular bioenergetics and cell survival. In addition, this work highlights metabolic vulnerabilities of cells in hypoxia, that could potentially be exploited for cancer therapy.
Supervisor: Anastasiou, D. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available