Mitochondrial Uncoupling Coordinated With PDH Activation Safely Ameliorates Hyperglycemia via Promoting Glucose Oxidation

作者：Haowen Jiang, Jia Jin, Yanan Duan, Zhifu Xie, Yufeng Li, Anhui Gao, Min Gu, Xinwen Zhang, Chang Peng, Chunmei Xia, Tiancheng Dong, Hui Li, Li-Fang Yu, Jie Tang, Fan Yang, Jingya Li, Jia Li · 发表于：Diabetes · 年份：2019 · DOI：10.2337/db19-0589 · 被引用次数：27 · 研究领域：Adipose Tissue and Metabolism、Mitochondrial Function and Pathology、Metabolomics and Mass Spectrometry Studies

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.