A Mitochondrial Pyruvate Carrier Required for Pyruvate Uptake in Yeast, Drosophila, and Humans

• Published in: Science (American Association for the Advancement of Science) Vol. 337; no. 6090; pp. 96 - 100
• Main Authors: Bricker, Daniel K., Taylor, Eric B., Schell, John C., Orsak, Thomas, Boutron, Audrey, Chen, Yu-Chan, Cox, James E., Cardon, Caleb M., Van Vranken, Jonathan G., Dephoure, Noah, Redin, Claire, Boudina, Sihem, Gygi, Steven P., Brivet, Michèle, Thummel, Carl S., Rutter, Jared
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 06.07.2012; The American Association for the Advancement of Science
• Subjects: Amino Acid Sequence; Amino acids; Amino Acids - metabolism; Animals; Anion Transport Proteins - chemistry; Anion Transport Proteins - genetics; Anion Transport Proteins - metabolism; Bacteria; Biochemistry, Molecular Biology; Biological and medical sciences; Biological Transport; Carbohydrate Metabolism; Carriers; Cell physiology; Citric Acid Cycle; Diet; Drosophila; Drosophila melanogaster - chemistry; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - chemistry; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Fundamental and applied biological sciences. Psychology; glycolysis; Human; Humans; Life Sciences; Medical schools; Membrane and intracellular transports; Metabolism; Metabolites; Metabolomics; mice; Mitochondria; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins - chemistry; Mitochondrial Membrane Transport Proteins - genetics; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Membranes - metabolism; Mitochondrial Proteins - chemistry; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Molecular and cellular biology; Molecular Sequence Data; Mutation; Oxidation; Oxidation-Reduction; Plasmids; Point Mutation; Proteins; Pyruvates; pyruvic acid; Pyruvic Acid - metabolism; Respiration; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Sugars; Transport; Transporter; tricarboxylic acid cycle; Yeast; Yeasts; Ascomycota; Human; Yeast; Cell organelle; Insecta; Biological transport; Pyruvate; Drosophilidae; Fungi; Transport process; Mitochondria; Arthropoda; Carboxylate; Invertebrata; Drosophila melanogaster; Saccharomyces cerevisiae; Diptera
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1218099

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.