Mitochondrial pyruvate supports lymphoma proliferation by fueling a glutamate pyruvate transaminase 2–dependent glutaminolysis pathway

Abstract

The fate of pyruvate is a defining feature in many cell types. One major fate is mitochondrial entry via the mitochondrial pyruvate carrier (MPC). We found that diffuse large B cell lymphomas (DLBCLs) consume mitochondrial pyruvate via glutamate-pyruvate transaminase 2 to enable α-ketoglutarate production as part of glutaminolysis. This led us to discover that glutamine exceeds pyruvate as a carbon source for the tricarboxylic acid cycle in DLBCLs. As a result, MPC inhibition led to decreased glutaminolysis in DLBCLs, opposite to previous observations in other cell types. We also found that MPC inhibition or genetic depletion decreased DLBCL proliferation in an extracellular matrix (ECM)–like environment and xenografts, but not in a suspension environment. Moreover, the metabolic profile of DLBCL cells in ECM is markedly different from cells in a suspension environment. Thus, we conclude that the synergistic consumption and assimilation of glutamine and pyruvate enables DLBCL proliferation in an extracellular environment-dependent manner.

Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells

“…Glutamate conversion to AKG can conventionally occur via three mitochondrial enzymes: GDH, which consumes glutamate and NAD +to generate AKG, NADH, and ammonia; GOT2, which converts glutamate and OAA to aspartate and AKG; and GPT2, which converts glutamate and pyruvate to AKG and alanine. The requirement for MPC1 to maintain AKG levels suggests that pyruvate-dependent GPT2 activity is a dominant route for AKG production in these cells, consistent with recent studies ( Figure 5—figure supplement 1A ; Rossiter et al, 2021 ; Wei et al, 2022 ; Weinberg et al, 2010 ). Indeed, MPC1 KO was also associated with a decrease in alanine levels, corroborating studies that identify GPT2 as a dominant source of alanine production ( Figure 5—figure supplement 1B ; Rossiter et al, 2021 ).…”

The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress

“…In addition, with increasing age, chondrocyte proliferation decreased, and mitochondrial senescence and dysfunction emerged, thereby increasing ROS production and the levels of fatty acids, glucose, and inflammation mediators and, eventually, cartilage damage [ 46 ]. α-KG is an essential metabolite of the mitochondrial TCA cycle that can regulate mitochondrial metabolism, antioxidation, and anti-inflammation [ [14] , [15] , [16] , [17] ], and its serum levels gradually decrease with age [ 30 ]. Accordingly, in the present study, we first quantified α-KG content in cartilage.…”

“…The tricarboxylic acid (TCA) cycle, also known as citric acid or Krebs cycle, occurs in the mitochondria in eukaryotes and regulates mitochondrial function and oxidative stress [ [14] , [15] , [16] , [17] ]. α-ketoglutarate (α-KG) is a key intermediate metabolite in the TCA cycle, also known as 2-oxoglutarate [ 18 ], which contributes to a variety of metabolic processes, including the biogenesis of numerous amino acids, nucleotide, lipid, and carnitine biosynthesis, and as a cofactor in numerous dioxygenases [ [19] , [20] , [21] , [22] ].…”

SLC25A51 impacts drug sensitivity in AML cells by sustaining mitochondrial oxidative flux

“…A recent study identified that an oxidative mitochondrial NAD + /NADH ratio was critical in ovarian cancer (42), and another reported that high SLC25A51 levels in hepatocellular carcinoma (HCC) promoted cancer progression through SIRT5 activation (43). Additionally, there are some phenotypic similarities between SLC25A51 loss in AML and block of mitochondrial pyruvate carrier in oxidative Non-Hodgkin Diffuse Large B Cell Lymphomas (44). It is possible that these carriers may function together to promote oxidative TCA flux in this blood cancer as well.…”