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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.
