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一种非经典的三羧酸循环为细胞身份提供了基础。

A non-canonical tricarboxylic acid cycle underlies cellular identity.

机构信息

Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, New York, NY, USA.

出版信息

Nature. 2022 Mar;603(7901):477-481. doi: 10.1038/s41586-022-04475-w. Epub 2022 Mar 9.

DOI:10.1038/s41586-022-04475-w
PMID:35264789
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8934290/
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 activity. 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.

摘要

三羧酸（TCA）循环是细胞代谢的中心枢纽，它将营养物质氧化为还原当量，用于能量产生和生物合成反应的关键代谢物。尽管 TCA 循环的产物对于细胞活力和增殖至关重要，但哺乳动物细胞的 TCA 循环活性存在多样性。这种多样性是如何产生的，以及它是否对建立细胞命运至关重要，目前仍知之甚少。在这里，我们发现了一种非典型的 TCA 循环，它是细胞状态变化所必需的。遗传共必需性图谱揭示了一组基因，这些基因足以组成一种生化替代经典 TCA 循环的途径，其中线粒体衍生的柠檬酸被运出到细胞质中，被 ATP 柠檬酸裂解酶代谢，最终再生线粒体草酰乙酸来完成这个非典型的 TCA 循环。在小鼠成肌细胞和胚胎干细胞中操纵 ATP 柠檬酸裂解酶或经典 TCA 循环酶 aconitase 2 的表达，揭示了 TCA 循环的结构变化伴随着细胞命运的转变。在从多能性中退出时，胚胎干细胞从经典 TCA 循环代谢转变为非典型 TCA 循环代谢。因此，阻断非典型 TCA 循环阻止细胞退出多能性。这些结果建立了一个依赖于上下文的传统 TCA 循环替代途径，并揭示了适当的 TCA 循环参与是细胞状态变化所必需的。

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