Tracking Reducing Equivalents Between Cellular Compartments to Understand the Metabolic Demands of Proliferation
Date of Award
Doctor of Philosophy (PhD)
Proliferating cancer cells compartmentalize metabolic reactions, many of which require reducing equivalents. This compartmentalization is functionally important, but it is challenging to study with current technologies. As a consequence, our understanding of proliferating metabolism has been limited. Here, I developed an approach to track reducing equivalents between cellular compartments. By applying this method to a panel of different cell lines under various conditions, I investigated a dysregulated metabolic phenotype in proliferating cells known as “aerobic glycolysis”. Aerobic glycolysis is characterized by an elevated rate of glucose fermentation to lactate irrespective of oxygen availability. Using the NCI-60 cell lines, I first determined that lactate excretion is strongly correlated with the activity of transferring reducing equivalents across the mitochondrial membrane, but not proliferation. Next, I found that aerobic glycolysis, a hallmark of cancer, is just a secondary consequence of saturating the activity of transferring reducing equivalents across the mitochondrial membrane rather than a unique metabolic driver of cellular proliferation. Therefore, the findings underscore the significance of transferring reducing equivalents across the mitochondrial membrane in proliferating cancer cells and highlight that my quantitative approach can be used to study compartmentalized NADH metabolism in various biochemical contexts.
Chair and Committee
Meredith Jackrel, Richard Loomis, Milan Chheda, Andrzej Krezel,
Wang, Yahui, "Tracking Reducing Equivalents Between Cellular Compartments to Understand the Metabolic Demands of Proliferation" (2022). Arts & Sciences Electronic Theses and Dissertations. 2817.
Available for download on Thursday, December 12, 2024