The mitochondrial permeability transition pore regulates nitric oxide-mediated apoptosis of neurons induced by target deprivation.
The mitochondrial permeability transition pore regulates nitric oxide-mediated apoptosis of neurons induced by target deprivation.
复制标题
线粒体通透性过渡孔调节靶剥夺引起的一氧化氮介导的神经元凋亡。
DOI：
10.1523/jneurosci.2225-10.2011
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发表时间：
2011-01-05
期刊：
影响因子：
--
通讯作者：
Wong M
中科院分区：
文献类型：
--
作者：
Martin LJ;Adams NA;Pan Y;Price A;Wong M
小鼠枕叶皮层消融诱导精确定时和统一的p53调制和approximately依赖性细胞凋亡的丘脑皮质投射神经元在背外侧膝状体核（LGN）损伤后7天。我们测试的假设，这种神经元凋亡是由氧化应激和线粒体通透性转换孔（mPTP）。凋亡前LGN神经元积累线粒体，Zn 2+和Ca 2+，并产生更高水平的活性氧（ROS），包括超氧化物，一氧化氮（NO）和过氧亚硝酸盐，比LGN神经元与一个完整的皮质目标。LGN神经元的凋亡前与蛋白质羰基化、蛋白质硝化和蛋白质S-亚硝基化的形成增加有关。一氧化氮合酶1（nos 1）的基因缺失和抑制NOS 1与硝基吲唑保护LGN神经元凋亡，揭示NO作为介质。mPTP的推定成分在小鼠LGN中表达，包括电压依赖性阴离子通道（VDAC）、腺嘌呤核苷酸转运体（ANT）和亲环蛋白D（CyPD）。皮质损伤后2天，LGN线粒体中CyPD和ANT发生硝化。化学交联显示LGN神经元凋亡前与CyPD和VDAC寡聚体的形成相关，与mPTP形成一致。没有CyPD的小鼠被从神经元凋亡中拯救出来，用mPTP抑制剂TRO-19622和TAT-Bcl-XL-BH 4治疗的小鼠也是如此。操纵的mPTP显着衰减的早期凋亡前产生的活性氧/氮物种在目标剥夺神经元。我们的研究结果表明，在成年小鼠脑神经元中，mPTP的功能，以提高ROS的生产和mPTP和NO触发细胞凋亡，因此，mPTP是在体内的神经保护的目标。
Ablation of mouse occipital cortex induces precisely timed and uniform p53-modulated and Bax-dependent apoptosis of thalamocortical projection neurons in the dorsal lateral geniculate nucleus (LGN) by 7 days postlesion. We tested the hypothesis that this neuronal apoptosis is initiated by oxidative stress and the mitochondrial permeability transition pore (mPTP). Pre-apoptotic LGN neurons accumulate mitochondria, Zn2+ and Ca2+, and generate higher levels of reactive oxygen species (ROS), including superoxide, nitric oxide (NO) and peroxynitrite, than LGN neurons with an intact cortical target. Pre-apoptosis of LGN neurons is associated with increased formation of protein carbonyls, protein nitration, and protein S-nitrosylation. Genetic deletion of nitric oxide synthase 1 (nos1) and inhibition of NOS1 with nitroindazole protected LGN neurons from apoptosis, revealing NO as a mediator. Putative components of the mPTP are expressed in mouse LGN, including the voltage-dependent anion channel (VDAC), adenine nucleotide translocator (ANT), and cyclophilin D (CyPD). Nitration of CyPD and ANT in LGN mitochondria occurs by 2 days after cortical injury. Chemical cross-linking showed that LGN neuron pre-apoptosis is associated with formation of CyPD and VDAC oligomers, consistent with mPTP formation. Mice without CyPD are rescued from neuron apoptosis as are mice treated with the mPTP inhibitors TRO-19622 and TAT-Bcl-XL-BH4. Manipulation of the mPTP markedly attenuated the early pre-apoptotic production of reactive oxygen/nitrogen species in target-deprived neurons. Our results demonstrate in adult mouse brain neurons that the mPTP functions to enhance ROS production and the mPTP and NO trigger apoptosis; thus, the mPTP is a target for neuroprotection in vivo.