Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits.
Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits.
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DOI：
10.1083/jcb.201605101
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发表时间：
2016-07-04
期刊：
影响因子：
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通讯作者：
Sheng ZH
中科院分区：
文献类型：
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作者：
Zhou B;Yu P;Lin MY;Sun T;Chen Y;Sheng ZH
Zhou等人表明，受损轴突中线粒体运动性降低和能量缺乏是导致成熟神经元再生失败的内在机制。虽然神经元再生是一个高能量需求的过程，轴突线粒体运输随着成熟而逐渐下降。成熟的神经元在损伤后通常不能再生，因此提出了一个根本性的问题，即线粒体运输是否是必要的，以满足再生过程中增强的代谢要求。在这里，我们揭示了受损轴突中线粒体运动性降低和能量不足是控制成熟神经元再生的内在机制。轴突切断诱导急性线粒体去极化和ATP耗竭损伤轴突。因此，成熟的神经元相关的神经锚定蛋白syntaphilin（SNPH）的增加和线粒体运输的减少导致局部能量不足。引人注目的是，通过基因操作增强线粒体运输通过补充受损轴突中的健康线粒体来促进再生能力，从而挽救能量不足。体内坐骨神经挤压研究进一步表明，snph基因敲除小鼠中线粒体转运增强可加速轴突再生。了解成熟神经元受损轴突中线粒体运输和能量供应的缺陷有助于开发刺激轴突再生的新策略。
Zhou et al. show that reduced mitochondrial motility and energy deficits in injured axons are intrinsic mechanisms contributing to regeneration failure in mature neurons. Although neuronal regeneration is a highly energy-demanding process, axonal mitochondrial transport progressively declines with maturation. Mature neurons typically fail to regenerate after injury, thus raising a fundamental question as to whether mitochondrial transport is necessary to meet enhanced metabolic requirements during regeneration. Here, we reveal that reduced mitochondrial motility and energy deficits in injured axons are intrinsic mechanisms controlling regrowth in mature neurons. Axotomy induces acute mitochondrial depolarization and ATP depletion in injured axons. Thus, mature neuron-associated increases in mitochondria-anchoring protein syntaphilin (SNPH) and decreases in mitochondrial transport cause local energy deficits. Strikingly, enhancing mitochondrial transport via genetic manipulation facilitates regenerative capacity by replenishing healthy mitochondria in injured axons, thereby rescuing energy deficits. An in vivo sciatic nerve crush study further shows that enhanced mitochondrial transport in snph knockout mice accelerates axon regeneration. Understanding deficits in mitochondrial trafficking and energy supply in injured axons of mature neurons benefits development of new strategies to stimulate axon regeneration.