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Letting Pyruvate In

Transport of pyruvate is an important event in metabolism whereby the pyruvate formed in glycolysis is transported into mitochondria to feed into the tricarboxylic acid cycle (see the Perspective by Murphy and Divakaruni). Two groups have now identified proteins that are components of the mitochondrial pyruvate transporter. Bricker et al. (p. 96, published online 24 May) found that the proteins mitochondrial pyruvate carrier 1 and 2 (MPC1 and MPC2) are required for full pyruvate transport in yeast and Drosophila cells and that humans with mutations in MPC1 have metabolic defects consistent with loss of the transporter. Herzig et al. (p. 93, published online 24 May) identified the same proteins as components of the carrier in yeast. Furthermore, expression of the mouse proteins in bacteria conferred increased transport of pyruvate into bacterial cells.

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.

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Table S1
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References and Notes

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Materials and methods are available as supplementary materials on Science Online.

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Published In

Science
Volume 337 | Issue 6090
6 July 2012

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Submission history

Received: 19 December 2011
Accepted: 9 May 2012
Published in print: 6 July 2012

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Acknowledgments

We thank members of the Rutter, Thummel, Winge, Stillman, Shaw, and Metzstein laboratories for helpful discussions. We thank the Shaw and Winge labs for the antibodies against Fzo1, Cyb2, and Mge1 and for the mito-RFP constructs. We thank J. M. Saudubray, L. Burglen, and H. Tevissen for referring patients and C. Thibault and J. L. Mandel (IGBMC, Strasbourg, France) for assistance in single-nucleotide polymorphism array hybridization. This research was supported by NIH grants R01GM083746 (J.R.), RC1DK086426 (C.S.T.), and R24DK092784 (J.R. and C.S.T.) and a pilot grant from P30DK072437 (J.R.). D.K.B. and C.M.C. were supported by the NIH Genetics Predoctoral Training Grant T32GM007464. E.B.T. was supported by NIH Pathway to Independence award K99AR059190. D.K.B., T.O., C.S.T., and J.R. are inventors on a patent application by the University of Utah covering the discovery of the MPC complex.

Authors

Affiliations

Daniel K. Bricker*
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Eric B. Taylor*
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
John C. Schell*
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Thomas Orsak*
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Audrey Boutron
Laboratoire de Biochimie, AP-HP Hôpital de Bicêtre, Le Kremlin Bicêtre, France.
Yu-Chan Chen
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
James E. Cox
Metabolomics Core Research Facility, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Caleb M. Cardon
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Jonathan G. Van Vranken
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Noah Dephoure
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Claire Redin
Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), Strasbourg, France.
Sihem Boudina
Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Steven P. Gygi
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Michèle Brivet
Laboratoire de Biochimie, AP-HP Hôpital de Bicêtre, Le Kremlin Bicêtre, France.
Carl S. Thummel
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Jared Rutter [email protected]
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.

Notes

*
These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: [email protected]

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