A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans.

TitleA mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans.
Publication TypeJournal Article
Year of Publication2012
AuthorsBricker, DK, Taylor, EB, Schell, JC, Orsak, T, Boutron, A, Chen, Y-C, Cox, JE, Cardon, CM, Van Vranken, JG, Dephoure, N, Redin, C, Boudina, S, Gygi, SP, Brivet, M, Thummel, CS, Rutter, J
JournalScience
Volume337
Issue6090
Pagination96-100
Date Published2012 Jul 6
ISSN1095-9203
KeywordsAmino Acid Sequence, Amino Acids, Animals, Anion Transport Proteins, Biological Transport, Carbohydrate Metabolism, Citric Acid Cycle, Drosophila melanogaster, Drosophila Proteins, Humans, Metabolomics, Mitochondria, Mitochondrial Membrane Transport Proteins, Mitochondrial Membranes, Mitochondrial Proteins, Molecular Sequence Data, Oxidation-Reduction, Point Mutation, Pyruvic Acid, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Abstract

Pyruvate constitutes a critical branch point in cellular carbon metabolism. We have identified two proteins, Mpc1 and Mpc2, as essential for mitochondrial pyruvate transport in yeast, Drosophila, and humans. 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. These data demonstrate that Mpc1 and Mpc2 form an essential part of the mitochondrial pyruvate carrier.

DOI10.1126/science.1218099
Alternate JournalScience
Citation Key10.1126/science.1218099
PubMed ID22628558
PubMed Central IDPMC3690818
Grant ListK99 AR059190 / AR / NIAMS NIH HHS / United States
K99AR059190 / AR / NIAMS NIH HHS / United States
P30 HL101310 / HL / NHLBI NIH HHS / United States
P30DK072437 / DK / NIDDK NIH HHS / United States
R01 DK071962 / DK / NIDDK NIH HHS / United States
R01 GM087346 / GM / NIGMS NIH HHS / United States
R01 GM094232 / GM / NIGMS NIH HHS / United States
R01GM083746 / GM / NIGMS NIH HHS / United States
R24 DK092784 / DK / NIDDK NIH HHS / United States
R24DK092784 / DK / NIDDK NIH HHS / United States
RC1DK086426 / DK / NIDDK NIH HHS / United States
T32GM007464 / GM / NIGMS NIH HHS / United States