PTPMT1 Inhibition Lowers Glucose through Succinate Dehydrogenase Phosphorylation.
PTPMT1 Inhibition Lowers Glucose through Succinate Dehydrogenase Phosphorylation.
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DOI：
10.1016/j.celrep.2015.01.010
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发表时间：
2015-02-10
期刊：
影响因子：
8.8
通讯作者：
Peterson RT
中科院分区：
文献类型：
--
作者：
Nath AK;Ryu JH;Jin YN;Roberts LD;Dejam A;Gerszten RE;Peterson RT
几乎所有的生物体都试图通过匹配燃料可用性和能量消耗来最大化适应性。在脊椎动物中，葡萄糖稳态是这一过程的核心，葡萄糖水平被精细地调整以匹配不断变化的能量需求。为了发现体内调节葡萄糖水平的新途径，我们在活斑马鱼中进行了大规模的化学筛选，并将小分子阿来西定鉴定为有效的降糖药物。我们发现阿来西定抑制PTEN样线粒体磷酸酶PTPMT1，并且其他使PTPMT1失活的药理学和遗传学手段也降低了斑马鱼的葡萄糖水平。ptpmt 1突变消除了阿来西定的作用，进一步证实了它是阿来西定的降糖靶点。然后，我们确定琥珀酸脱氢酶（SDH）作为底物的PTPMT 1。PTPMT1的失活导致SDH的过度磷酸化和激活，提供了PTPMT1协调葡萄糖稳态的可能机制。因此，PTPMT 1似乎是SDH磷酸化状态和葡萄糖浓度的重要调节剂。
Virtually all organisms seek to maximize fitness by matching fuel availability with energy expenditure. In vertebrates, glucose homeostasis is central to this process, with glucose levels finely tuned to match changing energy requirements. To discover new pathways regulating glucose levels in vivo, we performed a large-scale chemical screen in live zebrafish and identified the small molecule alexidine as a potent glucose-lowering agent. We found that alexidine inhibits the PTEN-like mitochondrial phosphatase PTPMT1, and that other pharmacological and genetic means of inactivating PTPMT1 also decrease glucose levels in zebrafish. Mutation of ptpmt1 eliminates the effect of alexidine, further confirming it as the glucose-lowering target of alexidine. We then identified succinate dehydrogenase (SDH) as a substrate of PTPMT1. Inactivation of PTPMT1 causes hyperphosphorylation and activation of SDH, providing a possible mechanism by which PTPMT1 coordinates glucose homeostasis. Therefore, PTPMT1 appears to be an important regulator of SDH phosphorylation status and glucose concentration.