The Importance of Mitochondrial Pyruvate Carrier in Cancer Cell Metabolism and Tumorigenesis

Abstract

Pyruvate is a key molecule in the metabolic fate of mammalian cells; it is the crossroads from where metabolism proceeds either oxidatively or ends with the production of lactic acid. Pyruvate metabolism is regulated by many enzymes that together control carbon flux. Mitochondrial pyruvate carrier (MPC) is responsible for importing pyruvate from the cytosol to the mitochondrial matrix, where it is oxidatively phosphorylated to produce adenosine triphosphate (ATP) and to generate intermediates used in multiple biosynthetic pathways. MPC activity has an important role in glucose homeostasis, and its alteration is associated with diabetes, heart failure, and neurodegeneration. In cancer, however, controversy surrounds MPC function. In some cancers, MPC upregulation appears to be associated with a poor prognosis. However, most transformed cells undergo a switch from oxidative to glycolytic metabolism, the so-called Warburg effect, which, amongst other possibilities, is induced by MPC malfunction or downregulation. Consequently, impaired MPC function might induce tumors with strong proliferative, migratory, and invasive capabilities. Moreover, glycolytic cancer cells secrete lactate, acidifying the microenvironment, which in turn induces angiogenesis, immunosuppression, and the expansion of stromal cell populations supporting tumor growth. This review examines the latest findings regarding the tumorigenic processes affected by MPC.

The Chemokine Receptor CCR5 Links Memory CD4+ T Cell Metabolism to T Cell Antigen Receptor Nanoclustering

“…Pyruvate kinases catalyze the irreversible transphosphorylation between phosphoenolpyruvate and adenosine diphosphate to form pyruvate, another rate-limiting step in glycolysis. There are several isoforms expressed in mammals, which differ in terms of substrate affinity and catalytic efficiency ( 47 ). PKM2 is upregulated in cells with a high anabolic profile since its dimeric form is less active.…”

Mitochondrial Carriers and Substrates Transport Network: A Lesson from Saccharomyces cerevisiae

“…Finally, the presence of a possible transporter for pyruvate, which does not seem to belong to MCF, is still a debated matter of research [56,57]. This transport protein, known as MPC (Mitochondrial Pyruvate Carrier), is a non-canonical mitochondrial carrier because it does not possess the structural and functional properties of the members of MCF [56].…”

“…This transport protein, known as MPC (Mitochondrial Pyruvate Carrier), is a non-canonical mitochondrial carrier because it does not possess the structural and functional properties of the members of MCF [56]. However, as canonical mitochondrial carrier proteins, MPC plays a central role in cellular homeostasis [57] since the transport of pyruvate into yeast mitochondria is an important step for oxidative energy metabolism as well as for the biosynthesis of organic compounds. In fact, in the mitochondrial matrix, pyruvate can be converted into acetyl-CoA by the pyruvate dehydrogenase complex, thus allowing the influx of carbon atoms into the Krebs cycle.…”

Immunometabolism Modulation in Therapy

“…In addition, cancer cells also downregulate the mitochondrial pyruvate carrier (MPC) complex, in charge of transporting pyruvate from the cytosol into the mitochondrial matrix. Reduced expression of MPC subunits causes the accumulation of pyruvate in the cytosol, thus favoring its conversion to lactate by lactate dehydrogenase (LDHA) [18]. Lactate is released to the TME via monocarboxylate transporter (MCT), and can be used as fuel by the cells.…”