Northeast Ohio Medical University, Rootstown, Ohio 44272 and.
School of Biomedical Science, Kent State University, Kent, Ohio 44242.
J Neurosci. 2018 May 30;38(22):5122-5139. doi: 10.1523/JNEUROSCI.3652-17.2018. Epub 2018 May 14.
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-, 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. A robust 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. We show axons in glaucomatous optic nerve are energy depleted and exhibit chronic metabolic stress. Underlying the metabolic stress are low levels of glucose and monocarboxylate transporters that compromise axon metabolism by limiting substrate availability. Axonal metabolic decline was reversed by upregulating monocarboxylate transporters as a result of placing the animals on a ketogenic diet. Optic nerve mitochondria responded capably to the oxidative phosphorylation necessitated by the diet and showed increased number. These findings indicate that the source of metabolic challenge can occur upstream of mitochondrial dysfunction. Importantly, the intervention was successful despite the animals being on the cusp of significant glaucoma progression.
轴突变性可能由代谢应激引起，这可能是线粒体功能障碍或缺乏适当底物输入的结果。在这项研究中，我们研究了 DBA/2J (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输送受损，后者基于我们观察到 D2 视神经 (ON)、人 ON 和急性青光眼损伤小鼠的葡萄糖和单羧酸转运体显著减少。我们将患有青光眼的 D2 雌雄小鼠和对照品系 DBA/2J-的小鼠置于生酮饮食中，以促进线粒体功能。 8 周的饮食产生了线粒体，通过逆转单羧酸转运体的下降来增加能量供应，减少胶质细胞肥大，保护视网膜神经节细胞及其轴突免受变性，并维持对大脑的生理信号。强烈的抗氧化反应也伴随着对饮食的反应。这些结果表明，D2 中的能量不足和随后的轴突变性是由于转运体下调导致的底物可用性降低引起的。我们表明，在青光眼视神经中，轴突能量耗尽并表现出慢性代谢应激。潜在的代谢应激是由于葡萄糖和单羧酸转运体水平低，通过限制底物可用性来损害轴突代谢。通过上调单羧酸转运体使动物处于生酮饮食状态，逆转了轴突代谢下降。视神经线粒体能够应对饮食所需的氧化磷酸化，并显示出数量增加。这些发现表明，代谢挑战的来源可能发生在线粒体功能障碍之前。重要的是，尽管动物处于严重青光眼进展的边缘，但干预仍然成功。
