In collaboration with Jean-Claude Martinou we were involved in the identification of mitochondrial pyruvate carrier, which imports pyruvate into the mitochondrial matrix, ending a 40-year search.
Figure: The transport activity of the reconstituted Mpc1 and Mpc3 hetero-dimer of yeast is delta-pH dependent.
In mammalians the mitochondrial pyruvate carrier consists of two protomers MPC1 and MPC2, each predicted to form a membrane protein with three transmembrane α-helices (blue, yellow and red) and a N-terminal amphipathic α-helix (white). Only co-expression of MPC1 and MPC2 in the cytoplasmic membrane of Lactococcus lactis results in uptake of pyruvate in whole cells, which could be inhibited by the specific inhibitor UK5099 . A dysfunctional mitochondrial pyruvate carrier causes mitochondrial disease with lactic acidosis and hyperpyruvatemia . Recently, we have managed to purify the yeast Mpc1/Mpc2 and Mpc1/Mpc3 complexes, showing that they form hetero-dimers, when co-expressed . When not engaged in hetero-dimers, the yeast Mpc proteins can also form homo-dimers, which are, however, inactive. The earlier described substrate transport properties and inhibitor profiles are embodied by the hetero-dimer. This work provides a foundation for elucidating the structure of the functional complex and the mechanism of substrate transport and inhibition.
We are interested in studying the mitochondrial pyruvate carrier, because many questions remain with respect to its structure, oligomeric state, kinetic properties, transport mechanism, physiological role and involvement in disease .
- (2012) Identification and functional expression of the mitochondrial pyruvate carrier. Science 337, 93-6
- (2012) A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science 337, 96-100
- (2019) The yeast mitochondrial pyruvate carrier is a hetero-dimer in its functional state. EMBO J 38
- (2015) Mitochondrial pyruvate import and its effects on homeostasis. Curr Opin Cell Biol 33, 35-41