The Experts below are selected from a list of 198 Experts worldwide ranked by ideXlab platform
Christian M Metallo - One of the best experts on this subject based on the ideXlab platform.
-
regulation of substrate utilization by the mitochondrial Pyruvate carrier
Molecular Cell, 2014Co-Authors: Nathaniel M Vacanti, Courtney R Green, Seth J Parker, Theodore P Ciaraldi, Robert R Henry, Anne N Murphy, Ajit S. Divakaruni, Christian M MetalloAbstract:Pyruvate lies at a central biochemical node connecting carbohydrate, amino acid, and fatty acid metabolism, and the regulation of Pyruvate flux into mitochondria represents a critical step in intermediary metabolism impacting numerous diseases. To characterize changes in mitochondrial substrate utilization in the context of compromised mitochondrial Pyruvate transport, we applied 13C metabolic flux analysis (MFA) to cells after transcriptional or pharmacological inhibition of the mitochondrial Pyruvate carrier (MPC). Despite profound suppression of both glucose and Pyruvate oxidation, cell growth, oxygen consumption, and tricarboxylic acid (TCA) metabolism were surprisingly maintained. Oxidative TCA flux was achieved through enhanced reliance on glutaminolysis through malic enzyme and Pyruvate dehydrogenase (PDH) as well as fatty acid and branched-chain amino acid oxidation. Thus, in contrast to inhibition of complex I or PDH, suppression of Pyruvate transport induces a form of metabolic flexibility associated with the use of lipids and amino acids as catabolic and anabolic fuels.
Shawn C Burgess - One of the best experts on this subject based on the ideXlab platform.
-
loss of mitochondrial Pyruvate carrier 2 in the liver leads to defects in gluconeogenesis and compensation via Pyruvate alanine cycling
Cell Metabolism, 2015Co-Authors: Kyle S Mccommis, Shawn C Burgess, Zhouji Chen, Xiaorong Fu, William G Mcdonald, Jerry R Colca, Rolf F Kletzien, Brian N FinckAbstract:Summary Pyruvate transport across the inner mitochondrial membrane is believed to be a prerequisite for gluconeogenesis in hepatocytes, which is important for the maintenance of normoglycemia during prolonged food deprivation but also contributes to hyperglycemia in diabetes. To determine the requirement for mitochondrial Pyruvate import in gluconeogenesis, mice with liver-specific deletion of mitochondrial Pyruvate carrier 2 (LS- Mpc2 −/− ) were generated. Loss of MPC2 impaired, but did not completely abolish, hepatocyte conversion of labeled Pyruvate to TCA cycle intermediates and glucose. Unbiased metabolomic analyses of livers from fasted LS- Mpc2 −/− mice suggested that alterations in amino acid metabolism, including Pyruvate-alanine cycling, might compensate for the loss of MPC2. Indeed, inhibition of Pyruvate-alanine transamination further reduced mitochondrial Pyruvate metabolism and glucose production by LS- Mpc2 −/− hepatocytes. These data demonstrate an important role for MPC2 in controlling hepatic gluconeogenesis and illuminate a compensatory mechanism for circumventing a block in mitochondrial Pyruvate import.
-
carbohydrate response element binding protein deletion alters substrate utilization producing an energy deficient liver
Journal of Biological Chemistry, 2008Co-Authors: Shawn C Burgess, Katsumi Iizuka, Nam Ho Jeoung, Robert A Harris, Yoshihiro Kashiwaya, Richard L Veech, Tatsuya Kitazume, Kosaku UyedaAbstract:Abstract Livers from mice lacking the carbohydrate-responsive element-binding protein (ChREBP) were compared with wild type (WT) mice to determine the effect of this transcription factor on hepatic energy metabolism. The Pyruvate dehydrogenase complex was considerably more active in ChREBP-/- mice because of diminished Pyruvate dehydrogenase kinase activity. Greater Pyruvate dehydrogenase complex activity caused a stimulation of lactate and Pyruvate oxidation, and it significantly impaired fatty acid oxidation in perfused livers from ChREBP-/- mice. This shift in mitochondrial substrate utilization led to a 3-fold reduction of the free cytosolic [NAD+]/[NADH] ratio, a 1.7-fold increase in the free mitochondrial [NAD+]/[NADH] ratio, and a 2-fold decrease in the free cytosolic [ATP]/[ADP][Pi] ratio in the ChREBP-/- liver compared with control. Hepatic Pyruvate carboxylase flux was impaired with ChREBP deletion secondary to decreased fatty acid oxidation, increased Pyruvate oxidation, and limited Pyruvate availability because of reduced activity of liver Pyruvate kinase and malic enzyme, which replenish Pyruvate via glycolysis and Pyruvate cycling. Overall, the shift from fat utilization to Pyruvate and lactate utilization resulted in a decrease in the energy of ATP hydrolysis and a hypo-energetic state in the livers of ChREBP-/- mice.
Kosaku Uyeda - One of the best experts on this subject based on the ideXlab platform.
-
carbohydrate response element binding protein deletion alters substrate utilization producing an energy deficient liver
Journal of Biological Chemistry, 2008Co-Authors: Shawn C Burgess, Katsumi Iizuka, Nam Ho Jeoung, Robert A Harris, Yoshihiro Kashiwaya, Richard L Veech, Tatsuya Kitazume, Kosaku UyedaAbstract:Abstract Livers from mice lacking the carbohydrate-responsive element-binding protein (ChREBP) were compared with wild type (WT) mice to determine the effect of this transcription factor on hepatic energy metabolism. The Pyruvate dehydrogenase complex was considerably more active in ChREBP-/- mice because of diminished Pyruvate dehydrogenase kinase activity. Greater Pyruvate dehydrogenase complex activity caused a stimulation of lactate and Pyruvate oxidation, and it significantly impaired fatty acid oxidation in perfused livers from ChREBP-/- mice. This shift in mitochondrial substrate utilization led to a 3-fold reduction of the free cytosolic [NAD+]/[NADH] ratio, a 1.7-fold increase in the free mitochondrial [NAD+]/[NADH] ratio, and a 2-fold decrease in the free cytosolic [ATP]/[ADP][Pi] ratio in the ChREBP-/- liver compared with control. Hepatic Pyruvate carboxylase flux was impaired with ChREBP deletion secondary to decreased fatty acid oxidation, increased Pyruvate oxidation, and limited Pyruvate availability because of reduced activity of liver Pyruvate kinase and malic enzyme, which replenish Pyruvate via glycolysis and Pyruvate cycling. Overall, the shift from fat utilization to Pyruvate and lactate utilization resulted in a decrease in the energy of ATP hydrolysis and a hypo-energetic state in the livers of ChREBP-/- mice.
Nathaniel M Vacanti - One of the best experts on this subject based on the ideXlab platform.
-
regulation of substrate utilization by the mitochondrial Pyruvate carrier
Molecular Cell, 2014Co-Authors: Nathaniel M Vacanti, Courtney R Green, Seth J Parker, Theodore P Ciaraldi, Robert R Henry, Anne N Murphy, Ajit S. Divakaruni, Christian M MetalloAbstract:Pyruvate lies at a central biochemical node connecting carbohydrate, amino acid, and fatty acid metabolism, and the regulation of Pyruvate flux into mitochondria represents a critical step in intermediary metabolism impacting numerous diseases. To characterize changes in mitochondrial substrate utilization in the context of compromised mitochondrial Pyruvate transport, we applied 13C metabolic flux analysis (MFA) to cells after transcriptional or pharmacological inhibition of the mitochondrial Pyruvate carrier (MPC). Despite profound suppression of both glucose and Pyruvate oxidation, cell growth, oxygen consumption, and tricarboxylic acid (TCA) metabolism were surprisingly maintained. Oxidative TCA flux was achieved through enhanced reliance on glutaminolysis through malic enzyme and Pyruvate dehydrogenase (PDH) as well as fatty acid and branched-chain amino acid oxidation. Thus, in contrast to inhibition of complex I or PDH, suppression of Pyruvate transport induces a form of metabolic flexibility associated with the use of lipids and amino acids as catabolic and anabolic fuels.
John C. Schell - One of the best experts on this subject based on the ideXlab platform.
-
control of intestinal stem cell function and proliferation by mitochondrial Pyruvate metabolism
Nature Cell Biology, 2017Co-Authors: John C. Schell, Dona R. Wisidagama, Claire Bensard, Helong Zhao, Aimee Flores, Jeffrey Mohlman, Lise K. Sorensen, Peng Wei, Jason M Tanner, Christian S. EarlAbstract:Most differentiated cells convert glucose to Pyruvate in the cytosol through glycolysis, followed by Pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial Pyruvate carrier (MPC), which is required for efficient mitochondrial Pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial Pyruvate oxidation. We sought to understand the role this transition from glycolysis to Pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial Pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells.
-
Control of intestinal stem cell function and proliferation by mitochondrial Pyruvate metabolism
Nature Cell Biology, 2017Co-Authors: John C. Schell, Dona R. Wisidagama, Claire Bensard, Helong Zhao, Jason Tanner, Aimee Flores, Jeffrey Mohlman, Lise K. Sorensen, Christian S. Earl, Kristofor A. OlsonAbstract:Schell et al. demonstrate that inactivation of the mitochondrial Pyruvate carrier in mouse and fly intestinal stem cells (ISCs) locks the cell into a glycolytic metabolic program and promotes the expansion of the stem cell compartment. Most differentiated cells convert glucose to Pyruvate in the cytosol through glycolysis, followed by Pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial Pyruvate carrier (MPC), which is required for efficient mitochondrial Pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial Pyruvate oxidation. We sought to understand the role this transition from glycolysis to Pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5 -EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial Pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells.
-
A mitochondrial Pyruvate carrier required for Pyruvate uptake in yeast, Drosophila, and humans.
Science, 2012Co-Authors: Daniel K. Bricker, Thomas Orsak, Yu Chan Chen, Caleb M. Cardon, Jonathan G. Van Vranken, Audrey Boutron, John C. Schell, Eric B. Taylor, Noah DephoureAbstract: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.