SUMMARY
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 α-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.
HIGHLIGHTS
Mitochondrial pyruvate supports glutaminolysis in DLBCLs by supplying pyruvate for GPT2-mediated α-KG production.
Glutamine, but not glucose, is a major carbon source for the TCA cycle in DLBCLs.
Citrate is minimally oxidized in the TCA cycle in DLBCLs.
MPC depletion decreases DLBCL growth in tumor xenograft assays.
α-KG production is important for DLBCLs proliferation in a solid ECM environment.
The mitochondrial pyruvate carrier supports DLBCL proliferation in a solid ECM environment.
Competing Interest Statement
The authors have declared no competing interest.