線粒體是細(xì)胞能量生成器,，對(duì)于生物體而言是一個(gè)非常重要的細(xì)胞器,，線粒體功能和很多疾病的發(fā)生發(fā)展密切相關(guān)，包括糖尿病和肥胖癥等代謝綜合癥。
近日，中科院上海藥物研究所在線粒體調(diào)節(jié)劑方面研究有新進(jìn)展,。李佳研究員課題組以線粒體膜電位作為線粒體功能指針，通過隨機(jī)篩選發(fā)現(xiàn)了低毒并且能濃度依賴性降低線粒體膜電位的小分子化合物C1,。C1能夠提高L6肌細(xì)胞內(nèi)AMP/ATP比率,，從而激活A(yù)MPK信號(hào)通路和促進(jìn)葡萄糖吸收。C1也能在HepG2肝癌細(xì)胞中激活A(yù)MPK信號(hào)通路并且降低脂含量,。在整體動(dòng)物實(shí)驗(yàn)中,，C1急性給藥能夠顯著提高呼吸熵并且在肝臟中激活A(yù)MPK信號(hào)通路；長期給藥實(shí)驗(yàn)表明,，C1能夠明顯降低糖尿病小鼠模型血漿中葡萄糖和游離脂肪酸含量,，腹腔注射糖耐量實(shí)驗(yàn)也進(jìn)一步證明C1能夠提高糖尿病小鼠的糖耐受力并且對(duì)糖異生也有明顯抑制作用。作用機(jī)制研究表明C1可能通過影響電子供體從而降低線粒體膜電位,，與之前報(bào)導(dǎo)的線粒體調(diào)節(jié)劑作用機(jī)制不同,。
該研究成果表明，通過尋找靶向線粒體功能的小分子調(diào)節(jié)劑,，可能獲得具有新穎機(jī)制的治療代謝綜合癥的先導(dǎo)化合物,，對(duì)進(jìn)一步闡明線粒體和代謝綜合癥的關(guān)系起到積極的意義,。該研究論文發(fā)表于國際糖尿病研究權(quán)威雜志《糖尿病》（Diabetes）,。（生物谷Bioon.com）
線粒體近期研究熱點(diǎn)：
Hepatology：線粒體解偶聯(lián)蛋白UCP2促進(jìn)肝損傷引起的細(xì)胞凋亡
PLoS ONE：線粒體基因缺失研究的最新進(jìn)展
Genome Research：線粒體基因組的選擇壓力與動(dòng)物運(yùn)動(dòng)能力相關(guān)
Nature：利用DNA核移植避免線粒體遺傳疾病
JBC：缺陷線粒體或能延緩衰老
線粒體有關(guān)實(shí)驗(yàn)方法：
線粒體的提取與觀察
線粒體腫脹檢測方法
線粒體熒光探針大全：TMRM，Mitotracker,，JC-1
細(xì)胞核與線粒體的分級(jí)分離
JC-1分析線粒體膜電位的方法
生物在線推薦：
線粒體試劑庫
生物谷推薦原始出處：
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.
