Leigh Syndrome (LS) is a mitochondrial disorder defined by progressive focal neurodegenerative lesions in specific regions of the brain. Defects in NDUFS4, a subunit of complex I of the mitochondrial electron transport chain, cause LS in humans; the Ndufs4 knockout mouse (Ndufs4(KO)) closely resembles the human disease. Here, we probed brain region-specific molecular signatures in pre-symptomatic Ndufs4(KO) to identify factors which underlie focal neurodegeneration. Metabolomics revealed that free amino acid concentrations are broadly different by region, and glucose metabolites are increased in a manner dependent on both region and genotype. We then tested the impact of the mTOR inhibitor rapamycin, which dramatically attenuates LS in Ndufs4(KO), on region specific metabolism. Our data revealed that loss of Ndufs4 drives pathogenic changes to CNS glutamine/glutamate/α-ketoglutarate metabolism which are rescued by mTOR inhibition Finally, restriction of the Ndufs4 deletion to pre-synaptic glutamatergic neurons recapitulated the whole-body knockout. Together, our findings are consistent with mTOR inhibition alleviating disease by increasing availability of α-ketoglutarate, which is both an efficient mitochondrial complex I substrate in Ndufs4(KO) and an important metabolite related to neurotransmitter metabolism in glutamatergic neurons.

中文翻译：

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Ndufs4(KO) 小鼠大脑中的区域代谢特征表明线粒体疾病中的谷氨酸/α-酮戊二酸代谢缺陷。

Leigh 综合征 (LS) 是一种线粒体疾病，由大脑特定区域的进行性局灶性神经退行性病变定义。NDUFS4（线粒体电子传递链复合物 I 的一个亚基）的缺陷会导致人类 LS；Ndufs4 基因敲除小鼠 (Ndufs4(KO)) 与人类疾病非常相似。在这里，我们探测了症状前 Ndufs4(KO) 中大脑区域特异性的分子特征，以确定局灶性神经变性的基础因素。代谢组学显示，游离氨基酸浓度因地区而异，葡萄糖代谢物的增加取决于地区和基因型。然后，我们测试了 mTOR 抑制剂雷帕霉素对区域特异性代谢的影响，它显着减弱了 Ndufs4(KO) 中的 LS。我们的数据显示，Ndufs4 的缺失驱动 CNS 谷氨酰胺/谷氨酸/α-酮戊二酸代谢的致病性变化，这些变化可以通过 mTOR 抑制来挽救。最后，将 Ndufs4 缺失限制在突触前谷氨酸能神经元中概括了全身敲除。总之，我们的研究结果与 mTOR 抑制通过增加 α-酮戊二酸的可用性来缓解疾病一致，α-酮戊二酸既是 Ndufs4（KO）中的有效线粒体复合物 I 底物，也是与谷氨酸能神经元中的神经递质代谢相关的重要代谢物。