Departments of Anatomy and Embryology, Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Cell Death Differ. 2013 Oct;20(10):1359-69. doi: 10.1038/cdd.2013.90. Epub 2013 Jul 12.
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 (H2O2), 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, H2O2-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.
酸感应离子通道 1a（ASIC1a）是神经系统中的关键质子受体，介导许多神经疾病中的酸中毒诱导的神经元损伤，如缺血性中风。到目前为止，功能性 ASIC1a 仅在质膜上发现。在这里，我们表明 ASIC1a 蛋白也存在于小鼠皮质神经元的线粒体中，它们与腺嘌呤核苷酸转运蛋白在物理上相关。此外，从 ASIC1a(-/-) 小鼠中纯化的线粒体表现出显著增强的 Ca(2+)保留能力和加速的 Ca(2+)摄取率。当受到过氧化氢 (H2O2) 挑战时，ASIC1a(-/-)神经元对细胞色素 c 释放和线粒体膜电位去极化具有抗性，表明由于 ASIC1a 缺失导致线粒体通透性转换 (MPT) 受损。一致地，H2O2 诱导的神经元死亡，其依赖于 MPT，在 ASIC1a(-/-)神经元中减少。此外，在 ASIC1a(-/-)小鼠大脑中检测到线粒体大小和氧化应激水平的显著增加，这也显示与活性氧信号通路密切相关的线粒体蛋白的表达发生了明显变化（>2 倍），如二维差异凝胶电泳随后进行质谱分析所揭示的。我们的数据表明，线粒体 ASIC1a 可能作为 MPT 孔的重要调节剂，有助于氧化应激诱导的神经元细胞死亡。
