Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma
Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma
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DOI：
10.1038/nm903
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发表时间：
2003-08-01
期刊：
影响因子：
82.9
通讯作者：
Wieloch, T
中科院分区：
文献类型：
--
作者：
Mattiasson, G;Shamloo, M;Wieloch, T
虽然解偶联蛋白 1 (UCP-1) 明显参与生热作用，但 UCP-2 的作用尚不清楚。使用杂交、克隆技术和 cDNA 阵列分析来鉴定可诱导的神经保护基因，我们发现神经元存活与 Ucp2 表达增加相关。在过度表达人 UCP-2 的小鼠中，实验性中风和创伤性脑损伤后的脑损伤减少，神经功能恢复得到增强。在培养的皮质神经元中，UCP-2 减少了细胞死亡并抑制了缺氧和缺糖诱导的 caspase-3 激活。 2,4-二硝基苯酚 (DNP) 的轻度线粒体解偶联减少了神经元死亡，而棕榈酸在分离的线粒体中增强了 UCP-2 活性。同样在分离的线粒体中，UCP-2 将活性氧的释放从线粒体基质转移到线粒体外空间。我们认为 UCP-2 是一种诱导蛋白，它通过激活细胞氧化还原信号或诱导轻度线粒体解偶联来防止凋亡蛋白的释放，从而具有神经保护作用。
Whereas uncoupling protein 1 (UCP-1) is clearly involved in thermogenesis, the role of UCP-2 is less clear. Using hybridization, cloning techniques and cDNA array analysis to identify inducible neuroprotective genes, we found that neuronal survival correlates with increased expression of Ucp2. In mice overexpressing human UCP-2, brain damage was diminished after experimental stroke and traumatic brain injury, and neurological recovery was enhanced. In cultured cortical neurons, UCP-2 reduced cell death and inhibited caspase-3 activation induced by oxygen and glucose deprivation. Mild mitochondrial uncoupling by 2,4-dinitrophenol (DNP) reduced neuronal death, and UCP-2 activity was enhanced by palmitic acid in isolated mitochondria. Also in isolated mitochondria, UCP-2 shifted the release of reactive oxygen species from the mitochondrial matrix to the extramitochondrial space. We propose that UCP-2 is an inducible protein that is neuroprotective by activating cellular redox signaling or by inducing mild mitochondrial uncoupling that prevents the release of apoptogenic proteins.