Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway.
Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway.
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DOI：
10.1016/j.cmet.2016.04.016
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发表时间：
2016-06-14
期刊：
影响因子：
29
通讯作者：
Rabinowitz JD
中科院分区：
文献类型：
--
作者：
Ducker GS;Chen L;Morscher RJ;Ghergurovich JM;Esposito M;Teng X;Kang Y;Rabinowitz JD
嘌呤和胸苷合成所需的一碳（1C）单位可通过细胞质或线粒体叶酸代谢由丝氨酸产生。线粒体1C途径在癌症中持续过度表达。在此我们表明，大多数（但并非所有）增殖的哺乳动物细胞系将线粒体途径作为产生1C单位的默认途径。CRISPR介导的线粒体途径敲除会激活细胞质1C单位的产生。细胞质通量的这种逆转是由一种单一代谢物（10 - 甲酰基 - 四氢叶酸）的耗尽所触发的，并且能使细胞在营养充足的条件下快速生长。然而，线粒体途径的缺失使细胞依赖细胞外丝氨酸来产生1C单位，并依赖细胞外甘氨酸来合成谷胱甘肽。缺乏线粒体1C途径活性的HCT - 116结肠癌异种移植物通过细胞质丝氨酸分解代谢产生生长所需的1C单位。两种途径均缺失则无法形成异种移植物。因此，线粒体或细胞质的1C代谢都可支持肿瘤发生，在营养缺乏条件下则需要线粒体途径。
通过遗传学和代谢组学方法，达克等人剖析了细胞质和线粒体叶酸代谢在细胞增殖中的作用，揭示出大多数细胞默认利用线粒体来产生1C单位，同时产生甘氨酸、NADH和NADPH。然而，在线粒体途径缺失时，细胞质代谢可支持肿瘤生长。
One-carbon (1C) units for purine and thymidine synthesis can be generated from serine by cytosolic or mitochondrial folate metabolism. The mitochondrial 1C pathway is consistently overexpressed in cancer. Here we show that most but not all proliferating mammalian cell lines use the mitochondrial pathway as the default for making 1C units. CRISPR-mediated mitochondrial pathway knockout activates cytosolic 1C-unit production. This reversal in cytosolic flux is triggered by depletion of a single metabolite, 10-formyl-THF, and enables rapid cell growth in nutrient-replete conditions. Loss of the mitochondrial pathway, however, renders cells dependent on extracellular serine to make 1C units and on extracellular glycine to make glutathione. HCT-116 colon cancer xenografts lacking mitochondrial 1C pathway activity generate the 1C units required for growth by cytosolic serine catabolism. Loss of both pathways precludes xenograft formation. Thus, either mitochondrial or cytosolic 1C metabolism can support tumorigenesis with the mitochondrial pathway required in nutrient poor conditions. Using genetic and metabolomic approaches, Ducker et al. dissect the roles of cytosolic and mitochondrial folate metabolism in cell proliferation, revealing that most cells default to mitochondria for making 1C units, simultaneously generating glycine, NADH and NADPH. Upon loss of the mitochondrial pathway, however, cytosolic metabolism supports tumor growth.