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Discovery and Mechanism Study of Mitochondrial Mild Uncoupler

Author: ChenDongMei
Tutor: LiJia
School: East China Normal University
Course: Biomedical
Keywords: mitochondria membrane potential high-throughput screening mild uncoupler
CLC: R341
Type: Master's thesis
Year: 2011
Downloads: 8
Quote: 0
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Abstract


Mitochondrion is one of the most important organelle in eukaryotic cells. In addition to supplying cellular energy, mitochondria are involved in a range of other processes, such as signaling, cellular differentiation and growth, and cell death. Mitochondria have been implicated in several human diseases, including diabetes, obesity, neurodegenerative diseases and cancer. Interest in mitochondrial biology has undergone a resurgence in recent years. Hence, we explored a strategy of targeting mitochondrial function to improve glucose and lipid metabolism.Mitochondrial membrane potential (MMP) in a marker of mitochondrial function, therefore we set up a high-throughput screening (HTS) assay of mitochondrial membrane potential in L6 myotubes. The effects of a selected lead compound were investigated in vitro and in vivo in related to metabolic syndrome. A novel small-molecule compound, LGH00272, was identified through this HTS. LGH00272 depolarized MMP in L6 myotubes without cytotoxicity and promoted the oxygen consumption mildly in cells and mitochondria in vitro. LGH00272 had no effect on the content of ATP and lactate in L6 myotubes, but increased the content of lactate mildly in HepG2 cells. In metabolic cells, LGH00272 enhanced glucose uptake and fatty acid oxidation in L6 myotubes, inhibited the glucose production in rat hepatocytes and reduced the contents of triglyceride and cholesterol in HepG2 cells. In DIO (diet induced obesity) mice, chronic administration of LGH00272 significantly reduced net body gain with no effects on food intake. LGH00272 also reduced hyperglycemia and the cholesterol in plasma, improved the glucose tolerance, and reduced the ratio of liver/BW (body weight) and fat/BW, and the mRNA levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in liver. Moreover, LGH00272 reduced the mRNA levels of fatty acid synthesis and increased the mRNA level of fatty acid oxidation.Our results demonstrate a novel mild uncoupler which mildly depolarized MMP, which 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 metabolic syndrome.

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