A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans.
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.
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Daniel K
DK
Bricker
Eric B
EB
Taylor
John C
JC
Schell
Thomas
T
Orsak
Audrey
A
Boutron
Yu-Chan
YC
Chen
James E
JE
Cox
Caleb M
CM
Cardon
Jonathan G
JG
Van Vranken
Noah
N
Dephoure
Claire
C
Redin
Sihem
S
Boudina
Steven P
SP
Gygi
Michèle
M
Brivet
Carl S
CS
Thummel
Jared
J
Rutter
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D027321:Anion Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D050260:Carbohydrate Metabolism; D002952:Citric Acid Cycle; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D055432:Metabolomics; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D027501:Monocarboxylic Acid Transporters; D010084:Oxidation-Reduction; D017354:Point Mutation; D019289:Pyruvic Acid / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D000596:Amino Acids; D027321:Anion Transport Proteins; D029721:Drosophila Proteins; C573715:FMP37 protein, S cerevisiae; C573719:MPC1 protein, Drosophila; C573718:MPC1 protein, human; C000595572:MPC2 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D027501:Monocarboxylic Acid Transporters; D029701:Saccharomyces cerevisiae Proteins; D019289:Pyruvic Acid