Structural and Functional Rescue of Chronic Metabolically Stressed Optic Nerves through Respiration
Structural and Functional Rescue of Chronic Metabolically Stressed Optic Nerves through Respiration
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DOI：
10.1523/jneurosci.3652-17.2018
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发表时间：
2018-05-30
影响因子：
5.3
通讯作者：
Inman, Denise M.
中科院分区：
文献类型：
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作者：
Harun-Or-Rashid, Mohammad;Pappenhagen, Nate;Inman, Denise M.
轴突变性可由代谢应激引起，可能是线粒体功能障碍或缺乏适当的底物输入的结果。在这项研究中，我们研究了在DBA/2 J（D2）青光眼模型中视神经病变期间观察到的代谢脆弱性是否是由于线粒体功能障碍或轴突底物递送受损，后者是基于我们观察到D2视神经（ON）、人ON和急性青光眼损伤小鼠中葡萄糖和单羧酸转运蛋白显著降低。我们将两种性别的D2小鼠和对照品系DBA/2 J-Gpnmb（+）小鼠置于生酮饮食中，以促进线粒体功能。八周的饮食产生线粒体，通过逆转单羧酸转运蛋白下降来改善能量可用性，减少胶质细胞肥大，保护视网膜神经节细胞及其轴突免于变性，并维持向大脑的生理信号。一个强大的抗氧化反应也伴随着对饮食的反应。这些结果表明，能量妥协和随后的轴突变性在D2是由于低底物的可用性继发于转运下调。
Axon degeneration can arise from metabolic stress, potentially a result of mitochondrial dysfunction or lack of appropriate substrate input. In this study, we investigated whether the metabolic vulnerability observed during optic neuropathy in the DBA/2J (D2) model of glaucoma is due to dysfunctional mitochondria or impaired substrate delivery to axons, the latter based on our observation of significantly decreased glucose and monocarboxylate transporters in D2 optic nerve ( ON), human ON, and mice subjected to acute glaucoma injury. We placed both sexes of D2 mice destined to develop glaucoma and mice of a control strain, the DBA/2J-Gpnmb(+), on a ketogenic diet to encourage mitochondrial function. Eight weeks of the diet generated mitochondria, improved energy availability by reversing monocarboxylate transporter decline, reduced glial hypertrophy, protected retinal ganglion cells and their axons from degeneration, and maintained physiological signaling to the brain. Arobust antioxidant response also accompanied the response to the diet. These results suggest that energy compromise and subsequent axon degeneration in the D2 is due to low substrate availability secondary to transporter downregulation.