噻唑烷二酮
线粒体
生物
生物化学
细胞生物学
内分泌学
糖尿病
2型糖尿病
作者
Jerry R. Colca,William Graham McDonald,Gregory S. Cavey,Serena L. Cole,Danielle D. Holewa,Angela S. Brightwell-Conrad,Cindy L. Wolfe,Jean S. Wheeler,Kristin R. Coulter,Peter M. Kilkuskie,Elena Gracheva,Yulia Korshunova,Michelle Trusgnich,Robert W. Karr,Sandra E. Wiley,Ajit S. Divakaruni,Anne N. Murphy,Patrick A. Vigueira,Brian N. Finck,Rolf F. Kletzien
出处
期刊:PLOS ONE
[Public Library of Science]
日期:2013-05-15
卷期号:8 (5): e61551-e61551
被引量:155
标识
DOI:10.1371/journal.pone.0061551
摘要
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 13C-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.
科研通智能强力驱动
Strongly Powered by AbleSci AI