title: Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier.
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 EC50 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.
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Divakaruni
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Wiley
authors.forename: George W
authors.initials: GW
authors.lastname: Rogers
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Andreyev
authors.forename: Susanna
authors.initials: S
authors.lastname: Petrosyan
authors.forename: Mattias
authors.initials: M
authors.lastname: Loviscach
authors.forename: Estelle A
authors.initials: EA
authors.lastname: Wall
authors.forename: Nagendra
authors.initials: N
authors.lastname: Yadava
authors.forename: Alejandro P
authors.initials: AP
authors.lastname: Heuck
authors.forename: David A
authors.initials: DA
authors.lastname: Ferrick
authors.forename: Robert R
authors.initials: RR
authors.lastname: Henry
authors.forename: William G
authors.initials: WG
authors.lastname: McDonald
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Colca
authors.forename: Melvin I
authors.initials: MI
authors.lastname: Simon
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Ciaraldi
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
mesh_terms: D000179:Acrylates / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D027321:Anion Transport Proteins; D015153:Blotting, Western; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D026901:Membrane Transport Proteins / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters; D018482:Muscle, Skeletal / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000070590:Solute Carrier Proteins; D045162:Thiazolidinediones / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000179:Acrylates; D027321:Anion Transport Proteins; C573718:MPC1 protein, human; C000595573:MPC1 pyruvate carrier protein, mouse; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D027501:Monocarboxylic Acid Transporters; C000629174:Mpc1 protein, rat; D000070590:Solute Carrier Proteins; D045162:Thiazolidinediones; C043654:2-cyano-3-(1-phenylindol-3-yl)acrylate; D045304:Cytochromes c; D005947:Glucose