Regulation of mitochondrial pyruvate uptake by alternative pyruvate carrier complexes

At the pyruvate branch point, the fermentative and oxidative metabolic routes diverge. Pyruvate can be transformed either into lactate in mammalian cells or into ethanol in yeast, or transported into mitochondria to fuel ATP production by oxidative phosphorylation. The recently discovered mitochondrial pyruvate carrier (MPC), encoded by MPC1, MPC2, and MPC3 in yeast, is required for uptake of pyruvate into the organelle. Here, we show that while expression of Mpc1 is not dependent on the carbon source, expression of Mpc2 and Mpc3 is specific to fermentative or respiratory conditions, respectively. This gives rise to two alternative carrier complexes that we have termed MPC FERM and MPC OX . By constitutively expressing the two alternative complexes in yeast deleted for all three endogenous genes, we show that MPC OX has a higher transport activity than MPC FERM , which is dependent on the C‐terminus of Mpc3. We propose that the alternative MPC subunit expression in yeast provides a way of adapting cellular metabolism to the nutrient availability. Synopsis Two alternative mitochondrial pyruvate carriers (MPCs) with distinct transport activities exist in yeast, and alternative MPC subunit expression is specific to fermentative or respiratory growth conditions, adapting cellular metabolism to nutrient availability. The active form of the mitochondrial pyruvate carrier in Saccharomyces cerevisiae is a heterodimer of either Mpc1 and Mpc2 (MPCFERM) or Mpc1 and Mpc3 (MPCOX). MPCFERM and MPCOX are expressed under fermentative and respiratory conditions, respectively. MPCOX has higher pyruvate transport activity than MPCFERM owing to differences in the C‐terminal region of Mpc2/Mpc3. The alternative expression of MPCFERM or MPCOX may be involved in the Crabtree effect of S. cerevisiae . Graphical Abstract Different growth conditions trigger the expression of alternative mitochondrial pyruvate carriers (MPCs) with distinct transport activities, allowing yeast cells to adapt cellular metabolism to nutrient availability.