1. Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)--relationship to newly identified mitochondrial pyruvate carrier proteins
- Author
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Yulia Korshunova, Angela S. Brightwell-Conrad, Jerry R. Colca, Brian N. Finck, Jean S. Wheeler, Ajit S. Divakaruni, Danielle D. Holewa, Serena L. Cole, Sandra E. Wiley, Kristin R. Coulter, Elena O. Gracheva, Michelle Trusgnich, Robert Karr, Cindy L. Wolfe, Peter M. Kilkuskie, Gregory S. Cavey, Anne N. Murphy, Rolf F. Kletzien, William G. McDonald, Patrick A. Vigueira, and Folli, Franco
- Subjects
Proteomics ,Anatomy and Physiology ,medicine.medical_treatment ,Pyruvate transport ,lcsh:Medicine ,Sequence Homology ,Drug action ,Mitochondrion ,Mitochondrial Membrane Transport Proteins ,chemistry.chemical_compound ,Endocrinology ,0302 clinical medicine ,Adipose Tissue, Brown ,Insulin Secretion ,Insulin ,Drug Interactions ,Thiazolidinedione ,lcsh:Science ,Inner mitochondrial membrane ,0303 health sciences ,Spectrometric Identification of Proteins ,Multidisciplinary ,biology ,Membrane transport protein ,Drosophila Melanogaster ,Acetyl-CoA ,Diabetes ,Animal Models ,3. Good health ,Mitochondria ,Amino Acid ,Drosophila melanogaster ,Biochemistry ,Adipose Tissue ,5.1 Pharmaceuticals ,Gene Knockdown Techniques ,Medicine ,Development of treatments and therapeutic interventions ,Research Article ,Monocarboxylic Acid Transporters ,Drugs and Devices ,Drug Research and Development ,medicine.drug_class ,General Science & Technology ,1.1 Normal biological development and functioning ,Molecular Sequence Data ,Endocrine System ,03 medical and health sciences ,Model Organisms ,Underpinning research ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Amino Acid Sequence ,Biology ,Metabolic and endocrine ,030304 developmental biology ,Diabetic Endocrinology ,Sequence Homology, Amino Acid ,lcsh:R ,Membrane Transport Proteins ,Brown ,Diabetes Mellitus Type 2 ,HEK293 Cells ,chemistry ,biology.protein ,lcsh:Q ,Thiazolidinediones ,Generic health relevance ,030217 neurology & neurosurgery - 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.
- Published
- 2013