Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin.
Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin.
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DOI：
10.1073/pnas.2014213117
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发表时间：
2020-12-29
影响因子：
11.1
通讯作者：
John SWM
中科院分区：
文献类型：
--
作者：
Harder JM;Guymer C;Wood JPM;Daskalaki E;Chidlow G;Zhang C;Balasubramanian R;Cardozo BH;Foxworth NE;Deering KE;Ouellette TB;Montgomery C;Wheelock CE;Casson RJ;Williams PA;John SWM
青光眼发病过程中视网膜神经节细胞对眼内压的易感性增加本文讨论了这些关系，并提供了一个更深入的了解这种常见的神经变性。我们证明了视网膜丙酮酸盐水平的眼内压依赖性下降与葡萄糖代谢失调相关，并在神经变性和代谢的机制联系中检测到mTOR激活。支持这一点，口服补充丙酮酸或雷帕霉素抑制mTOR强烈保护神经变性。因此，生物能量增强为神经退行性疾病提供了一种易于临床转化的策略。这项研究通过靶向可能反映在其他神经退行性疾病中的关键代谢途径，为青光眼的神经保护提供了重要途径，其中代谢失调可能起关键作用。眼内压力敏感性视网膜神经节细胞变性是青光眼的标志，青光眼是不可逆失明的主要原因。在这里，我们使用RNA测序和代谢组学来检查DBA/2 J小鼠的早期青光眼。我们证明了基因表达的变化，显着影响途径介导的代谢和葡萄糖和丙酮酸盐的运输。随后的代谢研究特征为视网膜丙酮酸水平的眼内压（IOP）依赖性下降，与可检测到的视神经变性前葡萄糖代谢失调相关。值得注意的是，视网膜葡萄糖水平升高了50倍，与糖酵解减少一致，但可能包括糖原动员和其他代谢变化。口服补充糖酵解产物丙酮酸在青光眼的大鼠和小鼠模型中都强烈地保护神经变性。进一步研究，我们在神经变性和代谢的机制联系中检测到mTOR激活。雷帕霉素诱导的mTOR抑制可有力地预防青光眼性神经变性，支持IOP诱导的mTOR激活在干扰代谢和促进青光眼中的破坏作用。总之，这些发现支持使用限制代谢紊乱和提供生物能量支持的治疗。这样的治疗提供了一个易于翻译的策略，值得在临床试验中进行研究。
Age-related bioenergetic insufficiency increases the vulnerability of retinal ganglion cells to intraocular pressure during glaucoma pathogenesis. This paper addresses these relationships and provides a deeper understanding of this common neurodegeneration. We demonstrate an intraocular pressure-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism, and detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Supporting this, oral supplementation of pyruvate or mTOR inhibition by rapamycin strongly protects from neurodegeneration. Bioenergetic enhancement thus provides a readily clinically translatable strategy for neurodegenerative disease. This study provides important avenues for neuroprotection against glaucoma by targeting key metabolic pathways that may be mirrored in other neurodegenerative diseases in which metabolic dysregulation may play a key role. Intraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Here, we used RNA-sequencing and metabolomics to examine early glaucoma in DBA/2J mice. We demonstrate gene expression changes that significantly impact pathways mediating the metabolism and transport of glucose and pyruvate. Subsequent metabolic studies characterized an intraocular pressure (IOP)-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Remarkably, retinal glucose levels were elevated 50-fold, consistent with decreased glycolysis but possibly including glycogen mobilization and other metabolic changes. Oral supplementation of the glycolytic product pyruvate strongly protected from neurodegeneration in both rat and mouse models of glaucoma. Investigating further, we detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration, supporting a damaging role for IOP-induced mTOR activation in perturbing metabolism and promoting glaucoma. Together, these findings support the use of treatments that limit metabolic disturbances and provide bioenergetic support. Such treatments provide a readily translatable strategy that warrants investigation in clinical trials.
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影响因子：
7.7
作者：
Qi, ZH;Fujita, H;Breyer, MD
通讯作者：
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影响因子：
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影响因子：
4.2
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通讯作者：
Hertz, Leif