ASIC1a channels regulate mitochondrial ion signaling and energy homeostasis in neurons
ASIC1a channels regulate mitochondrial ion signaling and energy homeostasis in neurons
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ASIC1a 通道调节神经元中的线粒体离子信号传导和能量稳态
DOI：
10.1111/jnc.14971
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发表时间：
2020-02-19
影响因子：
4.7
通讯作者：
Xu, Tian-Le
中科院分区：
文献类型：
--
作者：
Azoulay, Ivana Savic;Liu, Fan;Xu, Tian-Le
酸敏感离子通道1a（ASIC1a）是众所周知的发挥主要的病理生理作用，在脑缺血与急性酸中毒的pH值为6，而其功能在生理大脑活动，与更温和的pH值变化，仍然知之甚少。在这里，通过利用Na+和Ca2+敏感和空间特异性荧光染料进行活细胞成像，我们研究了ASIC1a在细胞溶质Na+和Ca2+信号中的作用，这些信号由pH 7.4至7.0的轻微细胞外下降引起，以及这些信号如何影响线粒体Na+和Ca2+信号或代谢活性。我们发现，在小鼠原代皮层神经元，这种小的细胞外pH值的变化触发胞质Na+和Ca2+波传播到线粒体。用Psalmotoxin 1或ASIC1a基因敲除抑制ASIC1a不仅阻断了胞浆Na+和Ca 2+信号，而且也阻断了线粒体Na+和Ca 2+信号。此外，ASIC1a的生理激活，这种pH值的变化，增强线粒体呼吸和唤起线粒体Na+信号，即使在毛地黄皂苷透性神经元。总之，我们的研究结果表明，ASIC1a是至关重要的连接生理细胞外pH刺激线粒体离子信号和代谢活动，因此是一个重要的代谢传感器。
Acid-sensing ion channel 1a (ASIC1a) is well-known to play a major pathophysiological role during brain ischemia linked to acute acidosis of pH 6, whereas its function during physiological brain activity, linked to much milder pH changes, is still poorly understood. Here, by performing live cell imaging utilizing Na+ and Ca2+ sensitive and spatially specific fluorescent dyes, we investigated the role of ASIC1a in cytosolic Na+ and Ca2+ signals elicited by a mild extracellular drop from pH 7.4 to 7.0 and how these affect mitochondrial Na+ and Ca2+ signaling or metabolic activity. We show that in mouse primary cortical neurons, this small extracellular pH change triggers cytosolic Na+ and Ca2+ waves that propagate to mitochondria. Inhibiting ASIC1a with Psalmotoxin 1 or ASIC1a gene knockout blocked not only the cytosolic but also the mitochondrial Na+ and Ca2+ signals. Moreover, physiological activation of ASIC1a by this pH shift enhances mitochondrial respiration and evokes mitochondrial Na+ signaling even in digitonin-permeabilized neurons. Altogether our results indicate that ASIC1a is critical in linking physiological extracellular pH stimuli to mitochondrial ion signaling and metabolic activity and thus is an important metabolic sensor.