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科学家发现细胞身份背后一个非经典的三羧酸循环
2022-03-13 16:27
来源：小柯机器人

美国斯隆—凯特林癌症研究所Lydia W. S. Finley团队发现细胞身份背后一个非经典的三羧酸循环。该项研究成果于2022年3月9日在线发表在《自然》杂志上。

研究人员确定了一个非经典的三羧酸（TCA）循环，它对细胞状态的变化是必需的。遗传共性图谱显示了一个基因簇，它足以组成一个替代经典TCA循环的生化方案，其中线粒体导出的柠檬酸盐被ATP柠檬酸酯酶代谢，最终再生线粒体草酰乙酸盐来完成这个非经典的TCA循环。通过在小鼠肌细胞和胚胎干细胞中操纵ATP柠檬酸酯酶或经典TCA循环酶aconitase 2的表达，研究人员发现TCA循环的配置变化伴随着细胞命运的转变。在脱离多能性的过程中，胚胎干细胞从经典的TCA周期代谢转换为非经典的TCA周期代谢。因此，阻断非经典TCA循环能阻止细胞退出多能性。这些结果为传统的TCA循环建立了一个依赖环境的替代方案，并揭示了适当的TCA循环参与对细胞状态的改变是必需的。
 
据悉，TCA循环是细胞代谢的中心枢纽，它氧化营养物质以产生用于能量生产的还原当量和用于生物合成反应的关键代谢物。尽管TCA循环的产物对细胞的活力和增殖很重要，但哺乳动物细胞在TCA循环的活性上显示出多样性。这种多样性是如何实现的，以及它是否是建立细胞命运的关键，仍不甚明了。
 
附：英文原文
 
Title: A non-canonical tricarboxylic acid cycle underlies cellular identity

Author: Arnold, Paige K., Jackson, Benjamin T., Paras, Katrina I., Brunner, Julia S., Hart, Madeleine L., Newsom, Oliver J., Alibeckoff, Sydney P., Endress, Jennifer, Drill, Esther, Sullivan, Lucas B., Finley, Lydia W. S.

Issue&Volume: 2022-03-09

Abstract: The tricarboxylic acid (TCA) cycle is a central hub of cellular metabolism, oxidizing nutrients to generate reducing equivalents for energy production and critical metabolites for biosynthetic reactions. Despite the importance of the products of the TCA cycle for cell viability and proliferation, mammalian cells display diversity in TCA-cycle activity1,2. How this diversity is achieved, and whether it is critical for establishing cell fate, remains poorly understood. Here we identify a non-canonical TCA cycle that is required for changes in cell state. Genetic co-essentiality mapping revealed a cluster of genes that is sufficient to compose a biochemical alternative to the canonical TCA cycle, wherein mitochondrially derived citrate exported to the cytoplasm is metabolized by ATP citrate lyase, ultimately regenerating mitochondrial oxaloacetate to complete this non-canonical TCA cycle. Manipulating the expression of ATP citrate lyase or the canonical TCA-cycle enzyme aconitase 2 in mouse myoblasts and embryonic stem cells revealed that changes in the configuration of the TCA cycle accompany cell fate transitions. During exit from pluripotency, embryonic stem cells switch from canonical to non-canonical TCA-cycle metabolism. Accordingly, blocking the non-canonical TCA cycle prevents cells from exiting pluripotency. These results establish a context-dependent alternative to the traditional TCA cycle and reveal that appropriate TCA-cycle engagement is required for changes in cell state. A non-canonical tricarboxylic acid cycle is required for changes in cell state.

DOI: 10.1038/s41586-022-04475-w

Source: https://www.nature.com/articles/s41586-022-04475-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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