| Summary: | To proliferate, tumors must synthesize sufficient biomass, such as proteins, nucleotides, and lipids. Many nutrients that produce biomass undergo oxidation reactions that require the redox cofactor NAD+ as an electron acceptor. Thus, the cellular redox state, measured by the NAD+/NADH ratio, can constrain the synthesis of oxidized biomass. This dissertation aims to uncover the determinants of the cellular NAD+/NADH ratio and how the cellular redox state governs biosynthetic capabilities of cancer cells in response to elevated biomass demands. In serine depleted conditions, which increase the NAD+ demand to support serine synthesis, we find that modulating the NAD+/NADH ratio proportionally alters serine synthesis rates. We uncover that some cancer cells elevate mitochondrial respiration and increase the NAD+/NADH ratio following serine withdrawal while others do not. Increasing mitochondrial respiration is sufficient to elevate the NAD+/NADH ratio and improve serine synthesis and proliferation in serine depleted conditions. Exogenous lipid withdrawal can also elevate mitochondrial respiration and the NAD+/NADH ratio, leading to increased serine synthesis despite no change in serine demand. Together, we find that the cellular NAD+/NADH ratio is regulated by mitochondrial respiration in a cell and environment specific manner, impacting oxidative biosynthesis reactions to determine the proliferative capacity of cancer cells in different nutrient environments.
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