The axon-protective WLD(S) protein partially rescues mitochondrial respiration and glycolysis after axonal injury.
The axon-protective WLD(S) protein partially rescues mitochondrial respiration and glycolysis after axonal injury.
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DOI：
10.1007/s12031-014-0440-2
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Coleman MP
中科院分区：
文献类型：
--
作者：
Godzik K;Coleman MP
轴突保护性沃勒氏变性慢蛋白(WLDS)可以改善轴突切断后轴突ATP水平的下降。在这里，我们测试了这一效应与维持线粒体呼吸和/或糖酵解有关的假设。我们用分离培养的颈上神经节(SCG)神经突起在海马XF-24代谢通量分析仪上测定了不同条件下线粒体的呼吸和糖酵解。我们观察到，在沃勒变性潜伏期，线粒体呼吸和糖酵解均显着下降。WLDS部分缓解了糖酵解和线粒体呼吸的下降。此外，我们还发现，在未切断的培养细胞中，耗尽NAD水平导致线粒体呼吸和糖酵解的变化，这与WLDS在切断后所恢复的改变类似，表明WLD S轴突在轴突损伤后NAD水平的维持至少部分是维持ATP水平的基础。然而，通过使用另一个轴突保护性突变(sarm1−/−)，我们可以证明挽救基础ECAR(因此可能是糖酵解)而不是基础OCR(线粒体呼吸)可能是延缓沃勒变性的保护性表型的一部分。这些发现为研究糖酵解以及轴突变性中NAD和ATP水平之间的联系开辟了新的途径，这可能有助于最终开发治疗神经退行性疾病的治疗策略。
The axon-protective Wallerian degeneration slow (WLDS) protein can ameliorate the decline in axonal ATP levels after neurite transection. Here, we tested the hypothesis that this effect is associated with maintenance of mitochondrial respiration and/or glycolysis. We used isolated neurites of superior cervical ganglion (SCG) cultures in the Seahorse XF-24 Metabolic Flux Analyser to determine mitochondrial respiration and glycolysis under different conditions. We observed that both mitochondrial respiration and glycolysis declined significantly during the latent phase of Wallerian degeneration. WLDS partially reduced the decline both in glycolysis and in mitochondrial respiration. In addition, we found that depleting NAD levels in uncut cultures led to changes in mitochondrial respiration and glycolysis similar to those rescued by WLDS after cut, suggesting that the maintenance of NAD levels in Wld S neurites after axonal injury at least partially underlies the maintenance of ATP levels. However, by using another axon-protective mutation (Sarm1 −/−), we could demonstrate that rescue of basal ECAR (and hence probably glycolysis) rather than basal OCR (mitochondrial respiration) may be part of the protective phenotype to delay Wallerian degeneration. These findings open new routes to study glycolysis and the connection between NAD and ATP levels in axon degeneration, which may help to eventually develop therapeutic strategies to treat neurodegenerative diseases.
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