The Role Of Mitochondrial Oxidative Phosphorylation On Glucose Metabolism

Objective: As mitochondria are the main subcellular organ devoted to ATP production and lipid oxidation,the role of mitochondrial function in the development of metabolic syndromes has been hotly debated.However,there was no consensus for the nature of mitochondrial dysfunction in the development of insulin resistance(IR).So the aim of this study was to gain more insight into the effect of high fat diet(HFD)on both liver and muscle mitochondrial function and the effect of inhibiting each complexes in mitochondrial oxidative phosphorylation(OXPHOS)system on glucose metabolism.Methods: 6 weeks old C57BL/6J male mice were randomized and fed with HFD or regular chow diet for 6 months,IPGTT and ITT experiments were conducted to test their glucose tolerance and insulin sensitivity.Liver and muscle mitochondrial function was assessed by measuring oxygen consumption rate,membrane potential,calcium retention capacity and citrate synthase activity in isolated mitochondria.After treating the Hep G2 hepatocytes and primary hepatocytes with each inhibitor of five complexes in mitochondrial OXPHOS system,the effect was assessed by detection of glucose consumption and lactate release or gluconeogenesis.Results: 1.HFD induced obesity,IR,impaired glucose tolerance and the increase of liver mitochondrial complex ? dependent oxygen consumption rate.HFD also cause the increase of both liver and muscle mitochondrial citrate synthase activity.2.Inhibition of mitochondrial complex ?,? and ATP synthase promoted glucose consumption and lactate release,and inhibition of mitochondrial complex ? reduces glucose consumption and lactate release in Hep G2 hepatocytes.The inhibition of mitochondrial complex ? decreased the glucose output of primary hepatocytes without any cytotoxicity.Conclusion: The metabolic syndromes caused by over-nutrition could enhanced partial mitochondrial oxidative phosphorylation,and inhibition of mitochondrial complex ? could improve glucose metabolism.