Restoring Cellular Energetics Promotes Axonal Regeneration and Functional Recovery after Spinal Cord Injury
Restoring Cellular Energetics Promotes Axonal Regeneration and Functional Recovery after Spinal Cord Injury
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DOI：
10.1016/j.cmet.2020.02.002
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发表时间：
2020-03-03
期刊：
影响因子：
29
通讯作者：
Xu, Xiao-Ming
中科院分区：
文献类型：
--
作者：
Han, Qi;Xie, Yuxiang;Xu, Xiao-Ming
中枢神经系统（CNS）轴突再生是一个高能量消耗的过程。外在的损伤和内在的限制导致损伤轴突的能量危机，这就提出了一个问题，即恢复能量不足是否有助于再生。在这里，我们发现通过删除突触蛋白（Snph）来增强轴突线粒体运输可以恢复损伤诱导的线粒体去极化。通过使用三种CNS损伤小鼠模型，我们证明Snph（-/-）小鼠通过脊髓损伤表现出增强的皮质脊髓束（CST）再生，单胺能轴突通过横断间隙加速再生，以及未损伤的CST代偿萌发增加。值得注意的是，再生的CST轴突形成功能性突触，促进运动功能恢复。在Snph（-/-）小鼠中，给予生物能量化合物肌酸可提高CST再生能力。我们的研究提供了中枢神经系统内在再生失败的机制，并表明增强线粒体运输和细胞能量是促进中枢神经系统损伤后再生和功能恢复的有希望的策略。
Axonal regeneration in the central nervous system (CNS) is a highly energy-demanding process. Extrinsic insults and intrinsic restrictions lead to an energy crisis in injured axons, raising the question of whether recovering energy deficits facilitates regeneration. Here, we reveal that enhancing axonal mitochondrial transport by deleting syntaphilin (Snph) recovers injury-induced mitochondrial depolarization. Using three CNS injury mouse models, we demonstrate that Snph(-/-) mice display enhanced corticospinal tract (CST) regeneration passing through a spinal cord lesion, accelerated regrowth of monoaminergic axons across a transection gap, and increased compensatory sprouting of uninjured CST. Notably, regenerated CST axons form functional synapses and promote motor functional recovery. Administration of the bioenergetic compound creatine boosts CST regenerative capacity in Snph(-/-) mice. Our study provides mechanistic in-sights into intrinsic regeneration failure in CNS and suggests that enhancing mitochondrial transport and cellular energetics are promising strategies to promote regeneration and functional restoration after CNS injuries.