Regional metabolic signatures in the Ndufs4(KO) mouse brain implicate defective glutamate/α-ketoglutarate metabolism in mitochondrial disease
Regional metabolic signatures in the Ndufs4(KO) mouse brain implicate defective glutamate/α-ketoglutarate metabolism in mitochondrial disease
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DOI：
10.1016/j.ymgme.2020.03.007
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发表时间：
2020-06-01
影响因子：
3.8
通讯作者：
Morgan, Philip G.
中科院分区：
文献类型：
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作者：
Johnson, Simon C.;Kayser, Ernst-Bernhard;Morgan, Philip G.
Leigh综合征（LS）是一种线粒体疾病，定义为大脑特定区域的进行性局灶性神经退行性病变。NDUFS 4（线粒体电子传递链复合物I的亚基）的缺陷导致人类LS; Ndufs 4敲除小鼠（Ndufs 4（KO））与人类疾病非常相似。在这里，我们探测了症状前Ndufs 4（KO）的大脑区域特异性分子特征，以确定局灶性神经变性的基础因素。代谢组学显示，游离氨基酸浓度在不同地区有很大差异，葡萄糖代谢产物以依赖于地区和基因型的方式增加。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，雷帕霉素显著减弱Ndufs 4（KO）中的LS。我们的数据显示，Ndufs 4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，其通过mTOR抑制来挽救。最后，将Ndufs 4缺失限制于突触前突触能神经元重演了全身敲除。总之，我们的发现与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Ndufs 4（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。
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/alpha-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 alpha-ketoglutarate, which is both an efficient mitochondrial complex I substrate in Ndufs4(KO) and an important metabolite related to neurotransmitter metabolism in glutamatergic neurons.