Metabolic remodeling: a pyruvate transport affair

Abstract

Metabolic remodeling is a major determinant for many cell fate decisions, and a switch from respiration to aerobic glycolysis is generally considered as a hallmark of cancer cell transformation. Pyruvate is a key metabolite at the major junction of carbohydrate metabolism between cytosolic glycolysis and the mitochondrial Krebs cycle. In this issue of The EMBO Journal, Bender et al show that yeast cells regulate pyruvate uptake into mitochondria, and thus its metabolic fate, by expressing alternative pyruvate carrier complexes with different activities.

Figure 1

The mitochondrial pyruvate carrier (MPC) at the junction between glycolytic and oxidative metabolism In respiring yeast, pyruvate produced from the non-fermentable carbon source glycerol is readily imported into the mitochondrial matrix by MPC_OX. Conversion of pyruvate to acetyl-CoA and its complete oxidation in the Krebs cycle drive high rates of oxidative phosphorylation (OXPHOS). In fermenting yeast, pyruvate transport into the matrix via the MPC_FERM complex is less efficient, resulting in the formation of ethanol from pyruvate in the cytosol. Glycolytic metabolites are used for the synthesis of biomolecules to support rapid cell proliferation. Aerobic glycolysis in cancer cells may be supported by down-regulation or post-translational modification of MPC subunits leading to reduced net uptake of pyruvate into mitochondria and formation of lactate in the cytosol. Cancer cells rely on glutamine oxidation to sustain the Krebs cycle in the mitochondrial matrix, which is a major source of material for anabolic metabolism and cell proliferation.