线粒体是细胞能量生成器，对于生物体而言是一个非常重要的细胞器，线粒体功能和很多疾病的发生发展密切相关，包括糖尿病和肥胖症等代谢综合症。
近日，中科院上海药物研究所在线粒体调节剂方面研究有新进展。李佳研究员课题组以线粒体膜电位作为线粒体功能指针，通过随机筛选发现了低毒并且能浓度依赖性降低线粒体膜电位的小分子化合物C1。C1能够提高L6肌细胞内AMP/ATP比率，从而激活AMPK信号通路和促进葡萄糖吸收。C1也能在HepG2肝癌细胞中激活AMPK信号通路并且降低脂含量。在整体动物实验中，C1急性给药能够显著提高呼吸熵并且在肝脏中激活AMPK信号通路；长期给药实验表明，C1能够明显降低糖尿病小鼠模型血浆中葡萄糖和游离脂肪酸含量，腹腔注射糖耐量实验也进一步证明C1能够提高糖尿病小鼠的糖耐受力并且对糖异生也有明显抑制作用。作用机制研究表明C1可能通过影响电子供体从而降低线粒体膜电位，与之前报导的线粒体调节剂作用机制不同。
该研究成果表明，通过寻找靶向线粒体功能的小分子调节剂，可能获得具有新颖机制的治疗代谢综合症的先导化合物，对进一步阐明线粒体和代谢综合症的关系起到积极的意义。该研究论文发表于国际糖尿病研究权威杂志《糖尿病》（Diabetes）。（生物谷Bioon.com）
线粒体近期研究热点：
Hepatology：线粒体解偶联蛋白UCP2促进肝损伤引起的细胞凋亡
PLoS ONE：线粒体基因缺失研究的最新进展
Genome Research：线粒体基因组的选择压力与动物运动能力相关
Nature：利用DNA核移植避免线粒体遗传疾病
JBC：缺陷线粒体或能延缓衰老
线粒体有关实验方法：
线粒体的提取与观察
线粒体肿胀检测方法
线粒体荧光探针大全：TMRM，Mitotracker，JC-1
细胞核与线粒体的分级分离
JC-1分析线粒体膜电位的方法
生物在线推荐：
线粒体试剂库
生物谷推荐原始出处：
Diabetes October 15, 2009, doi: 10.2337/db09-0223
A high-throughput assay for modulators of mitochondrial membrane potential identifies a novel compound with beneficial effects on db/db mice
Bei-Ying Qiu, BSc1, Nigel Turner, PhD2,3, Yuan-Yuan Li, BSc1, Min Gu, MSc1, Meng-Wei Huang, PhD4, Fang Wu, MSc1, Tao Pang, PhD1, Fa-Jun Nan, PhD1, Ji-Ming Ye, PhD2,5, Jing-Ya Li, PhD 1 and Jia Li, PhD 1
1National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
2Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia
3St Vincent's Hospital Clinical School, University of New South Wales, Sydney, NSW, Australia
4Roche R&D Center (China) Ltd., Shanghai, China
5School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Objective— Recently, several drugs have been shown to exert their beneficial effects for metabolic syndrome through mild regulation of mitochondrial function. Hence, we explored a strategy of targeting mitochondrial function to improve glucose and lipid metabolism.
Research design and methods— Mitochondrial membrane potential (Δψm) is a marker of mitochondrial function, therefore we set up a high-throughput screening (HTS) assay of Δψm in L6 myotubes. The effects of a selected lead compound were investigated in vitro and in vivo in relation to metabolic syndrome.
Results— A novel small-molecule compound, C1, was identified through this HTS. C1 depolarized Δψm in L6 myotubes without cytotoxicity and led to increased cellular AMP/ATP ratio, activation of AMP-activated protein kinase (AMPK) and enhanced glucose uptake. It also stimulated the AMPK pathway in HepG2 cells, leading to decreased lipid content. Intriguingly, C1 inhibited respiration in L6 myotubes, but did not affect respiration in isolated muscle mitochondria, suggesting that it may depolarize Δψm indirectly by affecting the supply of electron donors. Acute administration of C1 in C57BL/6J mice markedly increased fat oxidation and the phosphorylation of AMPK and ACC in the liver. In diabetic db/db mice, chronic administration of C1 significantly reduced hyperglycemia, plasma fatty acids, glucose intolerance and the mRNA levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in liver.
Conclusion— Our results demonstrate a novel small molecule which mildly depolarizes Δψm, is able to improve glucose and lipid metabolism to exert beneficial effects for metabolic syndrome. These findings suggest that compounds regulating mitochondrial function may have therapeutic potential for type 2 diabetes.
