Cited by 173Metabolism, Diabetes, and CancerMitochondrial Function and PathologyPeroxisome Proliferator-Activated Receptors

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Identification of a Mitochondrial Target of Thiazolidinedione Insulin Sensitizers (mTOT)—Relationship to Newly Identified Mitochondrial Pyruvate Carrier Proteins

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Colca, Jerry R., McDonald, William G., Cavey, Gregory S., Cole, Serena L., Holewa, Danielle D., Brightwell-Conrad, Angela S., Wolfe, Cindy L., Wheeler, Jean S., Coulter, Kristin R., Kilkuskie, Peter M., Gracheva, Elena, Korshunova, Yulia, Trusgnich, Michelle, Karr, Robert, Wiley, Sandra E., Divakaruni, Ajit S., Murphy, Anne N., Vigueira, Patrick A., Finck, Brian N., Kletzien, Rolf F.·2013·PLoS ONE

DOI 10.1371/journal.pone.0061551PMC PMC3655167

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Abstract

Thiazolidinedione (TZD) insulin sensitizers have the potential to effectively treat a number of human diseases, however the currently available agents have dose-limiting side effects that are mediated via activation of the transcription factor PPARγ. We have recently shown PPARγ-independent actions of TZD insulin sensitizers, but the molecular target of these molecules remained to be identified. Here we use a photo-catalyzable drug analog probe and mass spectrometry-based proteomics to identify a previously uncharacterized mitochondrial complex that specifically recognizes TZDs. These studies identify two well-conserved proteins previously known as brain protein 44 (BRP44) and BRP44 Like (BRP44L), which recently have been renamed Mpc2 and Mpc1 to signify their function as a mitochondrial pyruvate carrier complex. Knockdown of Mpc1 or Mpc2 in Drosophila melanogaster or pre-incubation with UK5099, an inhibitor of pyruvate transport, blocks the crosslinking of mitochondrial membranes by the TZD probe. Knockdown of these proteins in Drosophila also led to increased hemolymph glucose and blocked drug action. In isolated brown adipose tissue (BAT) cells, MSDC-0602, a PPARγ-sparing TZD, altered the incorporation of (13)C-labeled carbon from glucose into acetyl CoA. These results identify Mpc1 and Mpc2 as components of the mitochondrial target of TZDs (mTOT) and suggest that understanding the modulation of this complex, which appears to regulate pyruvate entry into the mitochondria, may provide a viable target for insulin sensitizing pharmacology.

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BindingDB (2020) · UC San Diego · doi:10.7270/q2xd14dj
BindingDB Entry 50007641: The Race to Bash NASH: Emerging Targets and Drug Development in a Complex Liver Disease.
BindingDB (2021) · UC San Diego · doi:10.7270/q2dj5jxg

Authors: Colca, J. R., McDonald, W. G., Cavey, G. S., Cole, S. L., Holewa, D. D., Brightwell-Conrad, A. S., Wolfe, C. L., Wheeler, J. S., Coulter, K. R., Kilkuskie, P. M., Gracheva, E., Korshunova, Y., Trusgnich, M., Karr, R., Wiley, S. E., Divakaruni, A. S., Murphy, A. N., Vigueira, P. A., Finck, B. N., & Kletzien, R. F.
Affiliations: Metabolic Solutions Development Company (United States) (US)
University of California San Diego (US)
Washington University in St. Louis (US)
Corresponding author: Colca, Jerry R.
ORCID: Colca, Jerry R.
Wiley, Sandra E.
Divakaruni, Ajit S.
Murphy, Anne N.
Vigueira, Patrick A.
Finck, Brian N.
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2013-05-15
Volume: 8
Issue: 5
Pages: e61551
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0061551
PMC: PMC3655167
OpenAlex: W2165311378
Cited by: 171
References: 30
Citations by year: 2026: 6 · 2025: 4 · 2024: 9 · 2023: 12 · 2022: 14 · 2021: 12 · 2020: 14 · 2019: 13 · 2018: 15 · 2017: 20 · 2016: 17 · 2015: 8 · 2014: 17 · 2013: 9
FWCI: 7.61
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS ONE (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
eScholarship (California Digital Library) (submittedVersion)
eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders: Michigan Economic Development Corporation
National Institutes of Health
National Institute on Alcohol Abuse and Alcoholism (AA21228, R42AA021228)
National Institute of Diabetes and Digestive and Kidney Diseases (R41DK084596, DK081298, DK84596, R42DK081298)
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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords: thiazolidinediones, insulin sensitizers, mitochondrial pyruvate carrier, MPC1, MPC2, pyruvate transport, acetyl-CoA biosynthesis, brown adipose tissue, hemolymph glucose, Drosophila melanogaster, drug target identification
MeSH terms: Insulin Secretion, Amino Acid Sequence, Animals, Adipose Tissue, Brown, Drosophila melanogaster, Humans, Hypoglycemic Agents, Insulin, Mitochondria, Molecular Sequence Data, Sequence Homology, Amino Acid, Membrane Transport Proteins, Monocarboxylic Acid Transporters, Mitochondrial Membrane Transport Proteins, Thiazolidinediones, Gene Knockdown Techniques, HEK293 Cells

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Identification of a Mitochondrial Target of Thiazolidinedione Insulin Sensitizers (mTOT)—Relationship to Newly Identified Mitochondrial Pyruvate Carrier Proteins

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