Alternative titles; symbols
HGNC Approved Gene Symbol: MPC2
Cytogenetic location: 1q24.2 Genomic coordinates (GRCh38): 1:167,916,675-167,937,072 (from NCBI)
In mitochondria, pyruvate is converted into acetyl-coenzyme A (acetyl-CoA) by the pyruvate dehydrogenase complex (see 300502). Uptake of pyruvate into mitochondria is mediated by a heterocomplex formed between MPC2 and MPC1 (614738) (Herzig et al., 2012).
By database analysis, Herzig et al. (2012) identified mouse and human MPC2. The deduced 127-amino acid human MPC2 protein has 3 transmembrane domains. MPC2 orthologs are present in a wide range of species, including yeast, bacteria, and plants. Yeast has 2 MPC2 orthologs, Mpc2 and Mpc3. Herzig et al. (2012) stated that, like MPC1 (BRP44L), MPC2 is an inner mitochondrial membrane protein.
Using yeast knockout and complementation assays, Herzig et al. (2012) found that Mpc1 and either Mpc2 or Mpc3 were required for mitochondrial pyruvate import in yeast. Coimmunoprecipitation studies revealed that yeast Mpc1 and Mpc2 interacted in a heterocomplex. Loss of pyruvate import in yeast deletion strains resulted in defects in pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase (see 613022) activities and in protein lipoylation. Expression of mouse Mpc1 alone could complement yeast lacking Mpc1, but expression of mouse Mpc2 alone failed to complement yeast lacking both Mpc2 and Mpc3. However, expression of mouse Mpc1 and Mpc2 together could complement yeast lacking both Mpc2 and Mpc3 or yeast lacking all 3 Mpc genes. Expression of mouse Mpc1 with mouse Mpc2, but neither protein alone, resulted in pyruvate uptake in Lactococcus lactis. Pyruvate uptake was sensitive to a mitochondrial pyruvate carrier inhibitor and to 2-deoxyglucose, which collapses the mitochondrial proton electrochemical gradient. Herzig et al. (2012) concluded that MPC1 and MPC2 function together as a mitochondrial pyruvate carrier.
Bricker et al. (2012) found that yeast or Drosophila mutants lacking Mpc1 displayed impaired pyruvate metabolism, with accumulation of upstream metabolites and depletion of tricarboxylic acid cycle intermediates. Yeast, Drosophila, or human MPC1, but not human MPC2, rescued the growth phenotype in Mpc1 mutant yeast. Silencing of Mpc1 or Mpc2 in mouse embryonic fibroblasts caused a modest decrease in pyruvate-driven oxygen consumption under basal conditions and a strong reduction when respiration was stimulated. Immunoprecipitation studies revealed that yeast Mpc1 and Mpc2 formed a complex of about 150 kD and that Mpc2 interacted with itself.
Hartz (2012) mapped the MPC2 gene to chromosome 1q24.2 based on an alignment of the MPC2 sequence (GenBank AL035304) with the genomic sequence (GRCh37).
Bricker, D. K., Taylor, E. B., Schell, J. C., Orsak, T., Boutron, A., Chen, Y.-C., Cox, J. E., Cardon, C. M., Van Vranken, J. G., Dephoure, N., Redin, C., Boudina, S., Gygi, S. P., Brivet, M., Thummel, C. S., Rutter, J. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science 337: 96-100, 2012. [PubMed: 22628558] [Full Text: https://doi.org/10.1126/science.1218099]
Hartz, P. A. Personal Communication. Baltimore, Md. 7/23/2012.
Herzig, S., Raemy, E., Montessuit, S., Veuthey, J.-L., Zamboni, N., Westermann, B., Kunji, E. R. S., Martinou, J.-C. Identification and functional expression of the mitochondrial pyruvate carrier. Science 337: 93-96, 2012. [PubMed: 22628554] [Full Text: https://doi.org/10.1126/science.1218530]