The neuromuscular junction (NMJ) is the largest, most-complex synapse in the human body. Motor neuron (MN) diseases, such as amyotrophic lateral sclerosis (ALS), specifically target MNs and the NMJs. However, little is known about the reasons for MN-selective neuronal and synaptic vulnerability in MN diseases. Here, utilizing a compartmental microfluidic in vitro co-culture system, we provide a possible explanation for why the NMJ, other than its unusual dimensions, differs from other synapses. By using live-imaging techniques, we discovered that cultured MNs display higher axonal and synaptic mitochondrial immobility compared with sympathetic neurons (SNs), leading to a profound enrichment of mitochondria only in the MN NMJ. Furthermore, by employing a synaptic ATP sensor, we show that mitochondrial respiration is the key contributor to ATP production in MN NMJs but not in SN synapses. Taken together, our data suggest that mitochondrial localization underlies the unique and specific qualities of MN NMJs. Our findings shed light on the role of mitochondria in MN and NMJ maintenance, and possibly indicate how mitochondria may serve as a source for selective MN vulnerability in neurodegenerative diseases.This article has an associated First Person interview with the first author of the paper.

中文翻译：

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体外隔室系统强调了线粒体固定性对NMJ中ATP供应的影响。

神经肌肉接头（NMJ）是人体中最大，最复杂的突触。运动神经元（MN）疾病，例如肌萎缩性侧索硬化症（ALS），特别针对MN和NMJ。然而，对于MN疾病中MN选择性神经元和突触脆弱性的原因知之甚少。在这里，利用隔室微流离体体外共培养系统，我们提供了一个可能的解释，说明NMJ除了其异常大小之外还不同于其他突触。通过使用实时成像技术，我们发现，与交感神经元（SN）相比，培养的MNs显示出更高的轴突和突触线粒体固定性，从而导致仅在MN NMJ中线粒体的富集。此外，通过采用突触ATP传感器，我们表明线粒体呼吸是MN NMJs，而不是SN突触中ATP产生的关键因素。综上所述，我们的数据表明线粒体定位是MN NMJ独特和特定质量的基础。我们的发现揭示了线粒体在MN和NMJ维持中的作用，并可能表明线粒体如何成为神经退行性疾病中选择性MN易感性的来源。