Mitochondrial Uncoupling Coordinated With PDH Activation Safely Ameliorates Hyperglycemia via Promoting Glucose Oxidation
Mitochondrial Uncoupling Coordinated With PDH Activation Safely Ameliorates Hyperglycemia via Promoting Glucose Oxidation
复制标题
线粒体解偶联与 PDH 激活相协调，通过促进葡萄糖氧化安全地改善高血糖。
DOI：
10.2337/db19-0589
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发表时间：
2019-12-01
期刊：
影响因子：
7.7
通讯作者：
Li, Jia
中科院分区：
文献类型：
--
作者：
Jiang, Haowen;Jin, Jia;Li, Jia
通过化学解偶联剂解偶联线粒体呼吸已被证明在改善肥胖、胰岛素抵抗和高血糖症中有效。然而，由于其潜在的致命不良反应，基于解偶联剂的治疗的发展仍然具有挑战性。在这里，我们确定丙酮酸脱氢酶（PDH）作为一个关键的修改器的毒性概况的2，4-二硝基苯酚（DNP），一个典型的线粒体解偶联剂。二氯乙酸（DCA）激活PDH可保护小鼠免于DNP诱导的高乳酸血症、高热和死亡，同时保留DNP促进燃料氧化和改善小鼠胰岛素敏感性的能力。从机制上讲，PDH激活开关线粒体葡萄糖氧化，以适应增加的糖酵解通量，导致在解偶联剂处理过程中乳酸分泌减少。我们设计了一种化学筛选策略，并发现化合物6 j是一种双重作用化合物，可以同时激活HH并解偶联线粒体呼吸。化合物6 j在恢复糖尿病小鼠的葡萄糖稳态方面表现出优异的功效和安全性。这项工作建立了一个新的原则，安全地利用化学解偶联剂的力量来治疗代谢性疾病。
Uncoupling of mitochondrial respiration by chemical uncouplers has proven effective in ameliorating obesity, insulin resistance, and hyperglycemia. However, development of uncoupler-based therapy remains challenging due to its potentially lethal adverse effects. Here, we identify pyruvate dehydrogenase (PDH) as a key modifier of the toxicity profile of 2, 4-dinitrophenol (DNP), a prototypical mitochondrial uncoupler. PDH activation by dichloroacetic acid (DCA) protects mice from DNP-induced hyperlactacidemia, hyperthermia, and death while preserving the ability of DNP to promote fuel oxidation and improve insulin sensitivity in mice. Mechanistically, PDH activation switches on mitochondrial glucose oxidation to accommodate increased glycolytic flux, leading to reduced lactate secretion during uncoupler treatments. We devised a chemical screening strategy and discovered compound 6j as a dual-action compound that simultaneously activates PDH and uncouples mitochondrial respiration. Compound 6j exhibits an excellent efficacy and safety profile in restoring glucose homeostasis in diabetic mice. This work establishes a new principle to safely harness the power of chemical uncouplers for the treatment of metabolic disease.