Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders.

中文翻译：

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线粒体损伤通过耗尽 NMNAT2 激活 Wallerian 通路，导致 SARM1 依赖性轴突变性。

物理损伤轴突的沃勒变性涉及一个明确的分子途径，将轴突存活因子 NMNAT2 的丧失与促退行性蛋白 SARM1 的激活联系起来。操纵通过这些蛋白质的途径导致通过类似沃勒的机制识别非轴突损伤导致轴突退化，包括一些涉及线粒体损伤的机制。线粒体功能障碍与帕金森病、Charcot-Marie-Tooth 病、遗传性痉挛性截瘫和其他轴突疾病密切相关。然而，线粒体损伤是否以及如何激活沃勒变性仍不清楚。在这里，我们发现线粒体膜电位的破坏导致小鼠交感神经元轴突 NMNAT2 的耗竭，增加这种 NAD 合成酶的底物与产物比率 (NMN/NAD)，这是沃勒变性的代谢指纹。该机制似乎涉及 NMNAT2 合成受损和轴突运输减少。WLDS 和 Sarm1 缺失的表达都在线粒体解偶联后保护轴突。阻断该通路还可以提供神经保护并延长具有 Pink1 功能丧失突变的果蝇的寿命，这会导致严重的线粒体缺陷。这些数据表明，线粒体损伤复制了沃勒变性的所有主要步骤，将其置于 NMNAT2 缺失的上游，有可能导致线粒体疾病的轴突病理学。该机制似乎涉及 NMNAT2 合成受损和轴突运输减少。WLDS 和 Sarm1 缺失的表达都在线粒体解偶联后保护轴突。阻断该通路还可以提供神经保护并延长具有 Pink1 功能丧失突变的果蝇的寿命，这会导致严重的线粒体缺陷。这些数据表明，线粒体损伤复制了沃勒变性的所有主要步骤，将其置于 NMNAT2 缺失的上游，有可能导致线粒体疾病的轴突病理学。该机制似乎涉及 NMNAT2 合成受损和轴突运输减少。WLDS 和 Sarm1 缺失的表达都在线粒体解偶联后保护轴突。阻断该通路还可以提供神经保护并延长具有 Pink1 功能丧失突变的果蝇的寿命，这会导致严重的线粒体缺陷。这些数据表明，线粒体损伤复制了沃勒变性的所有主要步骤，将其置于 NMNAT2 缺失的上游，有可能导致线粒体疾病的轴突病理学。