Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)--relationship to newly identified mitochondrial pyruvate carrier proteins.
Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)--relationship to newly identified mitochondrial pyruvate carrier proteins.
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DOI：
10.1371/journal.pone.0061551
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kletzien RF
中科院分区：
文献类型：
--
作者：
Colca JR;McDonald WG;Cavey GS;Cole SL;Holewa DD;Brightwell-Conrad AS;Wolfe CL;Wheeler JS;Coulter KR;Kilkuskie PM;Gracheva E;Korshunova Y;Trusgnich M;Karr R;Wiley SE;Divakaruni AS;Murphy AN;Vigueira PA;Finck BN;Kletzien RF
噻唑烷二酮（TZD）胰岛素增敏剂具有有效治疗许多人类疾病的潜力，然而目前可用的药物具有通过激活转录因子PPARγ介导的剂量限制性副作用。我们最近发现TZD胰岛素增敏剂的作用不依赖于PPARγ，但这些分子的分子靶点仍有待确定。在这里，我们使用光催化药物类似物探针和质谱为基础的蛋白质组学，以确定以前未知的线粒体复合物，特异性地识别TZDs。这些研究鉴定了两种高度保守的蛋白质，以前被称为脑蛋白44（BRP 44）和BRP 44样蛋白（BRP 44 L），最近被重新命名为Mpc 2和Mpc 1，以表明它们作为线粒体丙酮酸载体复合物的功能。敲低果蝇中的Mpc 1或Mpc 2或用丙酮酸转运抑制剂UK 5099预孵育，阻断TZD探针对线粒体膜的交联。在果蝇中敲除这些蛋白质也导致血淋巴葡萄糖增加和药物作用受阻。在分离的棕色脂肪组织（BAT）细胞中，MSDC-0602（一种保留PPARγ的TZD）改变了13 C标记的葡萄糖碳与乙酰辅酶A的结合。这些结果确定Mpc 1和Mpc 2作为TZDs（mTOT）的线粒体靶点的组分，并表明理解该复合物的调节，其似乎调节丙酮酸进入线粒体，可能为胰岛素增敏药理学提供可行的靶点。
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.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
16.2
作者：
DeFronzo RA;Abdul-Ghani M
通讯作者：
Abdul-Ghani M
DOI：
10.1056/nejmcibr1012075
发表时间：
2010-12-30
期刊：
The New England journal of medicine
影响因子：
--
作者：
Kahn BB;McGraw TE
通讯作者：
McGraw TE
影响因子：
4
作者：
Brun, RP;Spiegelman, BM
通讯作者：
Spiegelman, BM
影响因子：
4.8
作者：
Zuris, John A.;Ali, Syed S.;Jennings, Patricia A.
通讯作者：
Jennings, Patricia A.