Mechanism of mitochondrial dysfunction in diabetic sensory neuropathy
Mechanism of mitochondrial dysfunction in diabetic sensory neuropathy
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DOI：
10.1111/j.1085-9489.2003.03028.x
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发表时间：
2003-12-01
影响因子：
3.8
通讯作者：
Verkhratsky, A
中科院分区：
文献类型：
--
作者：
Fernyhough, P;Huang, TJ;Verkhratsky, A
对称性感觉性多发性神经病是人类糖尿病性神经病的最常见形式，与周围神经的一系列结构变化相关，包括轴突变性、结旁脱髓鞘和有髓纤维丢失-后者可能是远端轴突回退的结果。线粒体功能障碍最近被认为是这种周围神经系统退行性疾病的病因。基于对I型糖尿病动物模型的研究，已提出缺乏神经营养支持是糖尿病神经病变病因学的一个促成因素。我们最近发现，胰岛素和神经营养因子-3（NT-3）调节培养的成人感觉神经元线粒体膜电位。因此，我们测试的假设，糖尿病引起的线粒体功能障碍是由神经营养支持的损害。我们已经使用实时荧光视频显微镜分析线粒体膜电位在培养的成年感觉神经元分离正常和糖尿病大鼠。糖尿病引起的线粒体膜电位的显着损失，在所有亚群的感觉神经元，可以防止在体内治疗与胰岛素或NT-3。胰岛素和NT-3依赖性调节线粒体膜电位的机制涉及磷酸肌醇3激酶（PI 3激酶）途径的激活。PI 3激酶的下游靶点，如Akt和转录因子cAMP反应元件结合蛋白（CREB），被胰岛素和NT-3激活并调节感觉神经元基因表达。这些基因表达的改变调节代谢途径的关键组分和与神经元突触相关的电子传递链。我们的研究结果表明，在成年感觉神经元，胰岛素治疗可以提高输入的还原当量到线粒体电子传递链，这导致更大的线粒体膜极化和增强ATP合成。
Symmetrical sensory polyneuropathy, the most common form of diabetic neuropathy in humans, is associated with a spectrum of structural changes in peripheral nerve that includes axonal degeneration, paranodal demyelination, and loss of myelinated fibers - the latter probably the result of a dying-back of distal axons. Mitochondrial dysfunction has recently been proposed as an etiological factor in this degenerative disease of the peripheral nervous system. Lack of neurotrophic support has been proposed as a contributing factor in the etiology of diabetic neuropathy based on studies in animal models of Type I diabetes. We have recently demonstrated that insulin and neurotrophin-3 (NT-3) modulate mitochondrial membrane potential in cultured adult sensory neurons. We therefore tested the hypothesis that diabetes-induced mitochondrial dysfunction is caused by impairments in neurotrophic support. We have used real-time fluorescence video microscopy to analyze mitochondrial membrane potential in cultured adult sensory neurons isolated from normal and diabetic rats. Diabetes caused a significant loss of mitochondrial membrane potential in all sub-populations of sensory neurons which can be prevented by in vivo treatment with insulin or NT-3. The mechanism of insulin and NT-3-dependent modulation of mitochondrial membrane potential involves the activation of the phosphoinositide 3 kinase (PI 3 kinase) pathway. Downstream targets of PI 3 kinase, such as Akt and the transcription factor cAMP response element-binding protein (CREB), are activated by insulin and NT-3 and regulate sensory neuron gene expression. These alterations in gene expression modulate critical components of metabolite pathways and the electron transport chain associated with the neuronal mitochondrion. Our results show that in adult sensory neurons, treatment with insulin can elevate the input of reducing equivalents into the mitochondrial electron transport chain, which leads to greater mitochondrial membrane polarization and enhanced ATP synthesis.