A non-canonical convergence of carbohydrate and glutamine metabolism is required after metabolic rewiring in 3D environment

The fate of pyruvate, which is modulated mitochondrial pyruvate carrier (MPC) activity, is a defining metabolic feature in many cancers. Diffuse large B-cell lymphomas (DLBCLs) are a genetically and metabolically heterogenous cancer. Although MPC expression and activity differed between DLBCL subgroups, mitochondrial pyruvate oxidation was uniformly minimal. Mitochondrial pyruvate was instead robustly consumed by glutamate pyruvate transaminase 2 to support -ketoglutarate production as part of glutamine catabolism. This led us to discover that glutamine exceeds pyruvate as a carbon source for the TCA cycle, but, MPC function is required to enable GPT2-mediated glutamine catabolism. Furthermore, we found that MPC inhibition only decreased DLBCL proliferation in a solid culture environment, but not in a suspension environment. Thus, the non-canonical connection between the consumption and assimilation of carbohydrates and glutamine in DLBCLs enables their proliferation in a solid 3D environment. HIGHLIGHTSO_LIMitochondrial pyruvate supports glutaminolysis in DLBCLs by supplying pyruvate for GPT2-mediated -KG production. C_LIO_LIGlutamine, but not glucose, is a major carbon source for the TCA cycle in DLBCLs. C_LIO_LICitrate is minimally oxidized in the TCA cycle in DLBCLs. C_LIO_LI-KG production is important for DLBCLs proliferation in a 3D ECM environment. C_LIO_LIThe mitochondrial pyruvate carrier supports DLBCL proliferation in a 3D ECM environment. C_LI