期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 14, 页码 5422-5427出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1303360110
关键词
AMPK; pioglitazone; rosiglitazone; MSDC-0160; XF PMP
资金
- Department of Pharmacology, University of California at San Diego [P01HL085577]
- National Institutes of Health [R42DK081298, R24DK092154]
- American Diabetes Association [1-08-RA-139]
- Seahorse Bioscience
- Center for Excellence in Apoptosis Research translational funds from Massachusetts Technology Collaborative [A00000000004448]
- Defense Security Grant [7-05-DCSA-04]
- Department of Veterans Affairs Medical Research Service
- Ellison Medical Foundation [AG-SS-2190-08]
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.
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