Thiazolidinediones Are Acute, Specific Inhibitors of the Mitochondrial Pyruvate Carrier

Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5422-7. doi: 10.1073/pnas.1303360110. Epub 2013 Mar 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acrylates / pharmacology
  • Analysis of Variance
  • Animals
  • Anion Transport Proteins
  • Blotting, Western
  • Cell Line
  • Cell Respiration / drug effects*
  • Cytochromes c / metabolism
  • Glucose / metabolism
  • Humans
  • Membrane Potential, Mitochondrial / physiology
  • Membrane Transport Proteins / metabolism*
  • Metabolic Networks and Pathways / physiology*
  • Mice
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Membranes / metabolism*
  • Mitochondrial Proteins / antagonists & inhibitors*
  • Mitochondrial Proteins / metabolism
  • Monocarboxylic Acid Transporters
  • Muscle, Skeletal / metabolism
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Solute Carrier Proteins
  • Thiazolidinediones / metabolism
  • Thiazolidinediones / pharmacology*

Substances

  • Acrylates
  • Anion Transport Proteins
  • MPC1 protein, human
  • MPC1 pyruvate carrier protein, mouse
  • Membrane Transport Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • Monocarboxylic Acid Transporters
  • Mpc1 protein, rat
  • Solute Carrier Proteins
  • Thiazolidinediones
  • 2-cyano-3-(1-phenylindol-3-yl)acrylate
  • Cytochromes c
  • Glucose