Doctor of Philosophy

dissertationThe Mitochondrial Pyruvate Carrier (MPC) is an important carrier that transports pyruvate from cytosol into the mitochondria in a cell. Since its discovery, various studies have investigated the expression and impact of MPC in stem and cancer cells. Stem cell metabolism are often characterized by increased anaerobic glycolysis and a lower fraction of mitochondrial carbohydrate oxidation. Initially, the low mitochondrial carbohydrate oxidation feature had been thought to be induced by the environment, rather than an intrinsic feature determined by the cell itself. However, recent studies have revealed that metabolism is rather influential on stem cell fate. For instance, expression of the MPC, which often correlates with carbohydrate oxidation, is low in intestinal stem cells, but comparatively high in their differentiated progeny. Furthermore, deletion of MPC and reduced pyruvate oxidation enhances stem cell function and reinforces the stem cell markers expression. Despite this common understanding of MPC in stem cells, there is still no unified understanding of the relationship between a given type of cancer and its dependence on MPC. For example: re-expression of the MPC in colon cancer cells represses their tumor growth; while in prostate cancer and hepatocellular carcinoma, high MPC activity is required for their rapid proliferation. Diffuse large B-cell lymphoma (DLBCL) is the most common type of non- Hodgkin lymphoma. It is a heterogenous cancer type with different subgroups, such as iv Oxphos-DLBCLs and BCR-DLBCLs. However, the differences of carbohydrate metabolism across the two subgroups were unclear. Accordingly, we investigated the expression of the MPC in two DLBCL subgroups: Oxphos-DLBCLs and BCR-DLBCLs. Although MPC expression was higher in Oxphos-DLBCLs than BCR-DLCLs, we found both subgroups oxidized minimal pyruvate. Unexpectedly, mitochondrial pyruvate was mainly consumed to support α-ketoglutarate production, which, surprisingly, is the major carbon source feeding the TCA cycle in these cells. Furthermore, we discovered that MPC inhibition decreases DLBCL proliferation in a solid 3D environment, but not in a suspension environment. This is likely because MPC inhibition could not be compensated for by glutamate dehydrogenase in 3D environment. This metabolic program unveils a non-canonical connection between the consumption and assimilation of carbohydrates and glutamine