2.A.105 The Mitochondrial Pyruvate Carrier (MPC) Family
The transport of pyruvate, the end product of glycolysis, into mitochondria is an essential process that provides the organelle with a major oxidative fuel. Herzig et al. (2012) reported that MPC is a heterocomplex formed by two members of a family of previously uncharacterized membrane proteins that are conserved from yeast to mammals. Members of the MPC family are in the inner mitochondrial membrane, and yeast mutants lacking MPC proteins show severe defects in mitochondrial pyruvate uptake. Coexpression of mouse MPC1 and MPC2 in Lactococcus lactis promoted transport of pyruvate across the membrane (Herzig et al., 2012).
Mpc1 and Mpc2, are essential for mitochondrial pyruvate transport in yeast, Drosophila, and humans (Bricker et al., 2012). Mpc1 and Mpc2 associate to form an ~150-kilodalton complex in the inner mitochondrial membrane. Yeast and Drosophila mutants lacking MPC1 display impaired pyruvate metabolism, with an accumulation of upstream metabolites and a depletion of tricarboxylic acid cycle intermediates. Loss of yeast Mpc1 results in defective mitochondrial pyruvate uptake, and silencing of MPC1 or MPC2 in mammalian cells impairs pyruvate oxidation. A point mutation in MPC1 provides resistance to a known inhibitor of the mitochondrial pyruvate carrier. Human genetic studies of three families with children suffering from lactic acidosis and hyperpyruvatemia revealed a causal locus that mapped to MPC1, changing single amino acids that are conserved throughout eukaryotes. Thus, Mpc1 and Mpc2 form an essential part of the mitochondrial pyruvate carrier (Bricker et al., 2012). MPCs have been reviewed from historical and functional standpoints (McCommis and Finck 2015).