A Mitochondrial Pyruvate Carrier Required for Pyruvate Uptake in Yeast, Drosophila, and Humans
By Daniel K. Bricker, E. Taylor, John C. Schell, Thomas Orsak, A. Boutron, Yu-Chan Chen, James E. Cox, Caleb M. Cardon, Jonathan G. Van Vranken, Noah E. Dephoure and 6 more. Science, 2012
822 citations recorded by the source corpus.
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. The genes encoding two components of the pyruvate transporter in mitochondria have been identified. 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.
Subfields: Biochemistry, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/63f4ce9c64d9c6f22c17278995c25877e92ac177
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In Biochemistry
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Citations in the corpus
- Non-Alcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases (2017, neutral): “Mitochondrial pyruvate transport is regulated by two key related proteins, mitochondrial pyruvate carrier 1 and 2, which form a transport complex on the inner mitochondrial membrane (Bricker et al., 2012; Herzig et al., 2012).”
- Regulation of pyruvate metabolism and human disease (2013, background): “Specific reports have described defects in PDH, MPC, PDP, and PC causing or associated with neurological disorders [1, 68, 89, 90, 113, 127, 130].”
- Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport (2014, background): “Mammalian cells lacking functional MPC1 display normal 8 Molecular Cell 56, 1–11, November 6, 2014 ª2014 Elsevier Inc. glutamine-supported respiration (Bricker et al., 2012), consistent with our observation that glutamine supplies the TCA cycle in absence of pyruvate import.”
- The Science and Translation of Lactate Shuttle Theory. (2018, methodology): “Following reports of discovery of themPC (Bricker et al., 2012; Herzig et al., 2012), and with access to our own custom antibodies to MCT1 as well as commercially available antibodies to the putative mPC, we obtained images assessing colocalization of MCT1 and mPC in L6 cells.”
- Glutaminolysis: A Hallmark of Cancer Metabolism. (2017, background): “Mitochondrial pyruvate carrier (MPC) 1 and 2, embedded in the mitochondrial inner membrane, are essential for the transport of pyruvate into oxidation through the TCA cycle in yeast, Drosophila, and humans (9).”