Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death
Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death
复制标题
细胞内 ASIC1a 调节线粒体通透性转换依赖性神经元死亡
DOI：
10.1038/cdd.2013.90
复制
发表时间：
2013-10-01
影响因子：
12.4
通讯作者：
Xu, T-L
中科院分区：
文献类型：
--
作者：
Wang, Y-Z;Zeng, W-Z;Xu, T-L
酸敏感离子通道1a（Acid-sensing ion channel 1a，ASIC 1a）是神经系统中重要的质子受体，在缺血性脑卒中等神经系统疾病中介导酸中毒引起的神经元损伤。到目前为止，功能性ASIC 1a仅在质膜上发现。在这里，我们表明，ASIC 1a蛋白也存在于小鼠皮层神经元的线粒体中，在那里它们与腺嘌呤核苷酸移位酶物理相关。此外，纯化的ASIC 1a −/−小鼠线粒体表现出显著增强的Ca 2+滞留能力和加速的Ca 2+摄取速率。当受到过氧化氢（H2 O2）的攻击时，ASIC 1a −/−神经元对细胞色素c释放和线粒体内膜去极化具有抵抗性，这表明由于ASIC 1a缺失导致线粒体通透性转换（MPT）受损。同样，H2 O2诱导的神经元死亡，这是MPT依赖，减少在ASIC 1a −/−神经元。此外，在ASIC 1a −/−小鼠脑中检测到线粒体大小和氧化应激水平的显著增加，这也显示了与活性氧信号通路密切相关的线粒体蛋白表达的显著变化（> 2倍），如二维差异凝胶电泳和质谱分析所示。我们的数据表明，线粒体ASIC 1a可能作为一个重要的调节MPT孔，这有助于氧化神经元细胞死亡。
Acid-sensing ion channel 1a (ASIC1a) is the key proton receptor in nervous systems, mediating acidosis-induced neuronal injury in many neurological disorders, such as ischemic stroke. Up to now, functional ASIC1a has been found exclusively on the plasma membrane. Here, we show that ASIC1a proteins are also present in mitochondria of mouse cortical neurons where they are physically associated with adenine nucleotide translocase. Moreover, purified mitochondria from ASIC1a−/− mice exhibit significantly enhanced Ca 2+ retention capacity and accelerated Ca 2+ uptake rate. When challenged with hydrogen peroxide (H 2 O 2), ASIC1a−/− neurons are resistant to cytochrome c release and inner mitochondrial membrane depolarization, suggesting an impairment of mitochondrial permeability transition (MPT) due to ASIC1a deletion. Consistently, H 2 O 2-induced neuronal death, which is MPT dependent, is reduced in ASIC1a−/− neurons. Additionally, significant increases in mitochondrial size and oxidative stress levels are detected in ASIC1a−/− mouse brain, which also displays marked changes (> 2-fold) in the expression of mitochondrial proteins closely related to reactive oxygen species signal pathways, as revealed by two-dimensional difference gel electrophoresis followed by mass spectrometry analysis. Our data suggest that mitochondrial ASIC1a may serve as an important regulator of MPT pores, which contributes to oxidative neuronal cell death.