Department of Neuroinflammation, Institute of Neurology (Queen Square), University College London, 1 Wakefield Street, London, WC1N 1PJ, UK.
Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK.
J Neuroinflammation. 2018 Feb 27;15(1):61. doi: 10.1186/s12974-018-1094-8.
Small-diameter, myelinated axons are selectively susceptible to dysfunction in several inflammatory PNS and CNS diseases, resulting in pain and degeneration, but the mechanism is not known.
We used in vivo confocal microscopy to compare the effects of inflammation in experimental autoimmune neuritis (EAN), a model of Guillain-Barré syndrome (GBS), on mitochondrial function and transport in large- and small-diameter axons. We have compared mitochondrial function and transport in vivo in (i) healthy axons, (ii) axons affected by experimental autoimmune neuritis, and (iii) axons in which mitochondria were focally damaged by laser induced photo-toxicity.
Mitochondria affected by inflammation or laser damage became depolarized, fragmented, and immobile. Importantly, the loss of functional mitochondria was accompanied by an increase in the number of mitochondria transported towards, and into, the damaged area, perhaps compensating for loss of ATP and allowing buffering of the likely excessive Ca concentration. In large-diameter axons, healthy mitochondria were found to move into the damaged area bypassing the dysfunctional mitochondria, re-populating the damaged segment of the axon. However, in small-diameter axons, the depolarized mitochondria appeared to "plug" the axon, obstructing, sometimes completely, the incoming (mainly anterograde) transport of mitochondria. Over time (~ 2 h), the transported, functional mitochondria accumulated at the obstruction, and the distal part of the small-diameter axons became depleted of functional mitochondria.
The data show that neuroinflammation, in common with photo-toxic damage, induces depolarization and fragmentation of axonal mitochondria, which remain immobile at the site of damage. The damaged, immobile mitochondria can "plug" myelinated, small-diameter axons so that successful mitochondrial transport is prevented, depleting the distal axon of functioning mitochondria. Our observations may explain the selective vulnerability of small-diameter axons to dysfunction and degeneration in a number of neurodegenerative and neuroinflammatory disorders.
小直径有髓轴突在几种炎症性周围神经系统和中枢神经系统疾病中易发生功能障碍，导致疼痛和退化，但机制尚不清楚。
我们使用体内共聚焦显微镜比较实验性自身免疫性神经炎（EAN），格林-巴利综合征（GBS）的模型，对大直径和小直径轴突中线粒体功能和运输的影响。我们比较了（i）健康轴突、（ii）受实验性自身免疫性神经炎影响的轴突和（iii）通过激光诱导光毒性使线粒体局部受损的轴突中，线粒体的功能和运输。
受炎症或激光损伤影响的线粒体去极化、碎片化和不能运动。重要的是，功能性线粒体的丧失伴随着向受损区域运输和进入受损区域的线粒体数量增加，这可能补偿了 ATP 的损失，并允许缓冲可能过多的 Ca 浓度。在大直径轴突中，发现健康的线粒体绕过功能失调的线粒体进入受损区域，重新填充轴突受损的部分。然而，在小直径轴突中，去极化的线粒体似乎“堵塞”了轴突，有时完全阻塞了线粒体的传入（主要是顺行）运输。随着时间的推移（约 2 小时），运输的、功能正常的线粒体在阻塞处积聚，小直径轴突的远端部分失去了功能正常的线粒体。
数据表明，神经炎症与光毒性损伤一样，诱导轴突线粒体去极化和碎片化，受损线粒体在损伤部位保持不活动。受损的、不活动的线粒体可以“堵塞”有髓鞘的小直径轴突，从而阻止线粒体的成功运输，使远端轴突失去功能正常的线粒体。我们的观察结果可能解释了小直径轴突在多种神经退行性和神经炎症性疾病中易发生功能障碍和退化的选择性易感性。
