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葡萄糖衍生的谷氨酸在体外驱动神经元终末分化。

Glucose-derived glutamate drives neuronal terminal differentiation in vitro.

作者信息

D'Andrea Laura, Audano Matteo, Pedretti Silvia, Pelucchi Silvia, Stringhi Ramona, Imperato Gabriele, De Cesare Giulia, Cambria Clara, Laporte Marine H, Zamboni Nicola, Antonucci Flavia, Di Luca Monica, Mitro Nico, Marcello Elena

机构信息

Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Via Giuseppe Balzaretti 9, 20133, Milan, Italy.

Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Via F.lli Cervi 93, Segrate, 20054 Milan and via Vanvitelli 32, Milan, Italy.

出版信息

EMBO Rep. 2024 Mar;25(3):991-1021. doi: 10.1038/s44319-023-00048-8. Epub 2024 Jan 19.

DOI:10.1038/s44319-023-00048-8
PMID:38243137
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10933318/
Abstract

Neuronal maturation is the phase during which neurons acquire their final characteristics in terms of morphology, electrical activity, and metabolism. However, little is known about the metabolic pathways governing neuronal maturation. Here, we investigate the contribution of the main metabolic pathways, namely glucose, glutamine, and fatty acid oxidation, during the maturation of primary rat hippocampal neurons. Blunting glucose oxidation through the genetic and chemical inhibition of the mitochondrial pyruvate transporter reveals that this protein is critical for the production of glutamate, which is required for neuronal arborization, proper dendritic elongation, and spine formation. Glutamate supplementation in the early phase of differentiation restores morphological defects and synaptic function in mitochondrial pyruvate transporter-inhibited cells. Furthermore, the selective activation of metabotropic glutamate receptors restores the impairment of neuronal differentiation due to the reduced generation of glucose-derived glutamate and rescues synaptic local translation. Fatty acid oxidation does not impact neuronal maturation. Whereas glutamine metabolism is important for mitochondria, it is not for endogenous glutamate production. Our results provide insights into the role of glucose-derived glutamate as a key player in neuronal terminal differentiation.

摘要

神经元成熟是神经元在形态、电活动和代谢方面获得其最终特征的阶段。然而，关于调控神经元成熟的代谢途径却知之甚少。在此，我们研究了主要代谢途径，即葡萄糖、谷氨酰胺和脂肪酸氧化在原代大鼠海马神经元成熟过程中的作用。通过对线粒体丙酮酸转运体进行基因和化学抑制来减弱葡萄糖氧化，结果表明该蛋白对于谷氨酸的产生至关重要，而谷氨酸是神经元分支、适当的树突伸长和棘突形成所必需的。在分化早期补充谷氨酸可恢复线粒体丙酮酸转运体抑制细胞中的形态缺陷和突触功能。此外，代谢型谷氨酸受体的选择性激活可恢复因葡萄糖衍生谷氨酸生成减少而导致的神经元分化受损，并挽救突触局部翻译。脂肪酸氧化不影响神经元成熟。虽然谷氨酰胺代谢对线粒体很重要，但对内源性谷氨酸的产生并不重要。我们的研究结果为葡萄糖衍生谷氨酸作为神经元终末分化中的关键参与者的作用提供了见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/952f/10933318/55be4921c7c3/44319_2023_48_Fig13_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/952f/10933318/f706382a4e67/44319_2023_48_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/952f/10933318/6292470a9d6f/44319_2023_48_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/952f/10933318/59cbc76bca99/44319_2023_48_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/952f/10933318/70da5ff29eab/44319_2023_48_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/952f/10933318/64f2527ac935/44319_2023_48_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/952f/10933318/ac92dcb20092/44319_2023_48_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/952f/10933318/ac5507551fe2/44319_2023_48_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/952f/10933318/55be4921c7c3/44319_2023_48_Fig13_ESM.jpg

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