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 (SLC54) is a heterocomplex formed by two members of the MPC family 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). Yeast MPC proteins with an odd number of transmembrane segments and a matrix-exposed N-terminus are imported by the carrier pathway, using the receptor Tom70, small TIM chaperones, and the TIM22 complex. The TIM9.10 complex chaperones MPC proteins through the mitochondrial intermembrane space using conserved hydrophobic motifs that are also required for the interaction with canonical carrier proteins. Thus, the carrier pathway can import paired and non-paired TMSs and translocate N-termini to either side of the mitochondrial inner membrane, revealing an unexpected versatility of the mitochondrial import pathway for non-cleavable inner membrane proteins (Rampelt et al. 2020). The MPC family has been designated the SLC54 family (Gyimesi and Hediger 2020).

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).

Li et al. 2022 described the structures of yeast MPC1 and MPC2 reconstituted in dodecylphosphocholine (DPC) micelles and examined by NMR spectroscopy. They showed that both subunits contain three alpha-helical TMSs with substantial differences from what was predicted by AlphaFold2. The composition, structure, and function of the MPC complex has beendiscussed, and the different classes of small molecule inhibitors and their potential in therapeutics have been reviewed (Tavoulari et al. 2023).  Cyano-cinnamate derivatives are mitochondrial pyruvate carrier inhibitors (Huang et al. 2024).  Pyrazole-based inhibitors also target mitochondrial pyruvate carriers (Maram et al. 2025). Mitochondrial pyruvate carrier inhibitors for therapeutic applications have been reviewed (Politte et al. 2025).