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Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier
Open accessAbstract
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.
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“Since MSDC-0602 K retains a weak PPARγ binding affinity, the observed improvement in insulin sensitivity may not be solely mediated via MPC modulation [187].”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [187]
Experimental — accuracy not yet measuredIn the citing paper
“This shift is evident in cancer cells, which repress MPC1 to promote the Warburg Effect, and in myocytes of diabetic mice, which elevate glucose consumption in response to MPC inhibition22,23”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [23]
In the citing paper
“In fact, the MPC has emerged as an unanticipated target of thiazolidinediones (Colca et al., 2013; Divakaruni et al., 2013), a class of insulin sensitizing drugs, and as a regulator of insulin secretion (Patterson et al., 2014; Vigueira et al., 2014);”
From Regulation of Substrate Utilization by the Mitochondrial Pyruvate Carrier (2014) · cites this paper as Divakaruni et al., 2013
In the citing paper
“Knockdown of either Mpc1 or Mpc2 abrogated expression of both proteins, as observed previously (Divakaruni et al., 2013).”
From Regulation of Substrate Utilization by the Mitochondrial Pyruvate Carrier (2014) · cites this paper as Divakaruni et al., 2013
In the citing paper
“Our analyses also more explicitly delineate the roles of MPC1 and MPC2 as components of the mitochondrial pyruvate transporter.”
From Regulation of Substrate Utilization by the Mitochondrial Pyruvate Carrier (2014) · cites this paper as Divakaruni et al., 2013
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Self-citation
Metadata
- Authors
- Divakaruni, A. S., Wiley, S. E., Rogers, G. W., Andreyev, A. Y., Petrosyan, S., Loviscach, M., Wall, E. A., Yadava, N., Heuck, A. P., Ferrick, D. A., Henry, R. R., McDonald, W. G., Colca, J. R., Simon, M. I., Ciaraldi, T. P., & Murphy, A. N.
- Affiliations
- Departments of aPharmacology and
- Seahorse Bioscience, North Billerica, MA 01862;
- VA San Diego Healthcare System (US)
- Pioneer Valley Life Sciences Institute, Springfield, MA 01107;
- University of Massachusetts Amherst (US)
- University of California San Diego (US)
- Metabolic Solutions Development Company (United States) (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-03-19
- Volume
- 110
- Issue
- 14
- Pages
- 5422-5427
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3619368
- OpenAlex
- W1981961082
- Cited by
- 308
- References
- 58
- Citations by year
- 2026: 15 · 2025: 22 · 2024: 25 · 2023: 22 · 2022: 25 · 2021: 26 · 2020: 27 · 2019: 20 · 2018: 27 · 2017: 24 · 2016: 23 · 2015: 16 · 2014: 24 · 2013: 12
- FWCI
- 11.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (P01HL085577)
- National Institute of Diabetes and Digestive and Kidney Diseases (R42DK081298, R24DK092154)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- thiazolidinediones, mitochondrial pyruvate carrier, MPC1, MPC2, pyruvate transport, mitochondrial respiration inhibition, methyl pyruvate, glucose uptake, skeletal muscle fibers, insulin sensitization, metabolic dysfunction
- MeSH terms
- Solute Carrier Proteins, Acrylates, Analysis of Variance, Animals, Cell Line, Glucose, Humans, Blotting, Western, Muscle, Skeletal, Cell Respiration, Reverse Transcriptase Polymerase Chain Reaction, Mitochondrial Proteins, Membrane Transport Proteins, Anion Transport Proteins, Monocarboxylic Acid Transporters, Mitochondrial Membrane Transport Proteins, Thiazolidinediones, Cytochromes c, Mitochondrial Membranes, Mice, Rats, Membrane Potential, Mitochondrial, Metabolic Networks and Pathways
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