Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier
Contributed by Melvin I. Simon, February 21, 2013 (sent for review January 28, 2013)
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.
Acknowledgments
We thank the laboratory of Dr. Joan Heller Brown (Department of Pharmacology, University of California at San Diego) for providing isolated NRVMs (Grant P01HL085577), and Dr. Morton P. Printz (Department of Pharmacology, University of California at San Diego) for helpful discussions of our work. This work was supported by the National Institutes of Health (Grant R42DK081298); the American Diabetes Association (Grant 1-08-RA-139); Seahorse Bioscience (A.N.M.); Center for Excellence in Apoptosis Research translational funds from Massachusetts Technology Collaborative [Grant A00000000004448 (to N.Y. and A.P.H.)]; National Institutes of Health Grant R24DK092154, Defense Security Grant 7-05-DCSA-04, the Department of Veterans Affairs Medical Research Service (to R.R.H.); and the Ellison Medical Foundation [Grant AG-SS-2190-08 (to M.I.S.)].
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Freely available online through the PNAS open access option.
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Published online: March 19, 2013
Published in issue: April 2, 2013
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Acknowledgments
We thank the laboratory of Dr. Joan Heller Brown (Department of Pharmacology, University of California at San Diego) for providing isolated NRVMs (Grant P01HL085577), and Dr. Morton P. Printz (Department of Pharmacology, University of California at San Diego) for helpful discussions of our work. This work was supported by the National Institutes of Health (Grant R42DK081298); the American Diabetes Association (Grant 1-08-RA-139); Seahorse Bioscience (A.N.M.); Center for Excellence in Apoptosis Research translational funds from Massachusetts Technology Collaborative [Grant A00000000004448 (to N.Y. and A.P.H.)]; National Institutes of Health Grant R24DK092154, Defense Security Grant 7-05-DCSA-04, the Department of Veterans Affairs Medical Research Service (to R.R.H.); and the Ellison Medical Foundation [Grant AG-SS-2190-08 (to M.I.S.)].
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Competing Interests
Conflict of interest statement: G.W.R. and D.A.F. are employees of Seahorse Bioscience, which has provided a new reagent for use in the present study. J.R.C. is a cofounder and shareholder of Metabolic Solutions Development Co., and W.G.M. is an employee and shareholder of Metabolic Solutions Development Co.
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Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier, Proc. Natl. Acad. Sci. U.S.A.
110 (14) 5422-5427,
https://doi.org/10.1073/pnas.1303360110
(2013).
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