1. Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier
- Author
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Alexander Y. Andreyev, Alejandro P. Heuck, William G. McDonald, Melvin I. Simon, Robert R. Henry, Estelle A. Wall, Theodore P. Ciaraldi, Sandra E. Wiley, Mattias Loviscach, Nagendra Yadava, David A. Ferrick, Ajit S. Divakaruni, Susanna Petrosyan, George W. Rogers, Anne N. Murphy, and Jerry R. Colca
- Subjects
Monocarboxylic Acid Transporters ,Pyruvate dehydrogenase kinase ,Cellular respiration ,Glucose uptake ,Anion Transport Proteins ,Blotting, Western ,Cell Respiration ,Pyruvate transport ,PKM2 ,Mitochondrial Membrane Transport Proteins ,Cell Line ,Mitochondrial Proteins ,Mice ,Mitochondrial pyruvate transport ,Animals ,Humans ,Muscle, Skeletal ,Inner mitochondrial membrane ,Membrane Potential, Mitochondrial ,Solute Carrier Proteins ,Analysis of Variance ,Multidisciplinary ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Membrane transport protein ,Cytochromes c ,Membrane Transport Proteins ,Biological Sciences ,Rats ,Glucose ,Acrylates ,Biochemistry ,Mitochondrial Membranes ,biology.protein ,Thiazolidinediones ,Metabolic Networks and Pathways - Abstract
Facilitated pyruvate transport across the mitochondrial inner membrane is a critical step in carbohydrate, amino acid, and lipid metabolism. We report that clinically relevant concentrations of thiazolidinediones (TZDs), a widely used class of insulin sensitizers, acutely and specifically inhibit mitochondrial pyruvate carrier (MPC) activity in a variety of cell types. Respiratory inhibition was overcome with methyl pyruvate, localizing the effect to facilitated pyruvate transport, and knockdown of either paralog, MPC1 or MPC2, decreased the EC 50 for respiratory inhibition by TZDs. Acute MPC inhibition significantly enhanced glucose uptake in human skeletal muscle myocytes after 2 h. These data ( i ) report that clinically used TZDs inhibit the MPC, ( ii ) validate that MPC1 and MPC2 are obligatory components of facilitated pyruvate transport in mammalian cells, ( iii ) indicate that the acute effect of TZDs may be related to insulin sensitization, and ( iv ) establish mitochondrial pyruvate uptake as a potential therapeutic target for diseases rooted in metabolic dysfunction.
- Published
- 2013
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