Nucleic acid and histone modifications critically depend on central metabolism for substrates and co-factors. Although a few enzymes related to the formation of these required metabolites have been reported in the nucleus, the corresponding metabolic pathways are considered to function elsewhere in the cell. Here we show that a substantial part of the mitochondrial tricarboxylic acid (TCA) cycle, the biosynthetic hub of epigenetic modification factors, is operational also in the nucleus. Using 13C-tracer analysis, we identified activity of glutamine-to-fumarate, citrate-to-succinate, and glutamine-to-aspartate routes in the nuclei of HeLa cells. Proximity labeling mass-spectrometry revealed a spatial vicinity of the involved enzymes with core nuclear proteins, supporting their nuclear location. We further show nuclear localization of aconitase 2 and 2-oxoglutarate dehydrogenase in mouse embryonic stem cells. Together, our results demonstrate operation of an extended metabolic pathway in the nucleus warranting a revision of the canonical view on metabolic compartmentalization and gene expression regulation.

中文翻译：

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TCA循环子网在哺乳动物核中的运行

核酸和组蛋白的修饰主要取决于底物和辅助因子的中央代谢。尽管已经在细胞核中报道了与这些必需代谢物形成相关的几种酶，但认为相应的代谢途径在细胞中的其他部位起作用。在这里，我们显示了线粒体三羧酸（TCA）循环的大部分（表观遗传修饰因子的生物合成中心）也在核中起作用。使用13C示踪剂分析，我们确定了HeLa细胞核中谷氨酰胺转化为富马酸盐，柠檬酸盐转化为琥珀酸盐以及谷氨酰胺转化为天冬氨酸的活性。接近标记质谱法揭示了所涉及酶与核心核蛋白的空间邻近性，支持了它们的核位置。我们进一步显示在小鼠胚胎干细胞中乌头酸酶2和2-氧戊二酸脱氢酶的核定位。在一起，我们的结果表明在核中扩展的代谢途径的运作保证了对代谢区室化和基因表达调控的规范观点的修订。