美国加州大学洛杉矶分校Heather R. Christofk小组发现，天冬酰胺可连接线粒体呼吸与ATF4活性和肿瘤生长。该项研究成果于2021年2月19日在线发表在《细胞—代谢》上。

研究人员发现，除消耗细胞内的天冬氨酸外，电子传输链（ETC）抑制作用还消耗天冬氨酸衍生的天冬酰胺，增加了ATF4的水平，并损害了mTOR复合体I（mTORC1）的活性。外源天冬酰胺可在ETC抑制的情况下恢复增殖、ATF4和mTORC1活性以及mTORC1依赖的核苷酸合成，这表明天冬酰胺可将主动呼吸传递给ATF4和mTORC1。

最后，研究人员发现，ETC抑制剂二甲双胍（其限制肿瘤天冬酰胺的合成）与天冬酰胺酶或饮食天冬酰胺的限制（其限制肿瘤天冬酰胺的消耗）的组合能够有效地阻碍多种癌症小鼠模型中的肿瘤生长。因为环境天冬酰胺足以在呼吸障碍的情况下恢复肿瘤生长，所以这项发现表明天冬酰胺的合成是肿瘤线粒体呼吸的基本目的，可用于癌症患者的治疗。 

据介绍，线粒体呼吸对于细胞增殖至关重要。除产生ATP外，呼吸还产生生物合成的前体，例如天冬氨酸，这是核苷酸合成的重要底物。

附：英文原文

Title: Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth

Author: Abigail S. Krall, Peter J. Mullen, Felicia Surjono, Milica Momcilovic, Ernst W. Schmid, Christopher J. Halbrook, Apisadaporn Thambundit, Steven D. Mittelman, Costas A. Lyssiotis, David B. Shackelford, Simon R.V. Knott, Heather R. Christofk

Issue&Volume: 2021-02-19

Abstract: Mitochondrial respiration is critical for cell proliferation. In addition to producingATP, respiration generates biosynthetic precursors, such as aspartate, an essentialsubstrate for nucleotide synthesis. Here, we show that in addition to depleting intracellularaspartate, electron transport chain (ETC) inhibition depletes aspartate-derived asparagine,increases ATF4 levels, and impairs mTOR complex I (mTORC1) activity. Exogenous asparaginerestores proliferation, ATF4 and mTORC1 activities, and mTORC1-dependent nucleotidesynthesis in the context of ETC inhibition, suggesting that asparagine communicatesactive respiration to ATF4 and mTORC1. Finally, we show that combination of the ETCinhibitor metformin, which limits tumor asparagine synthesis, and either asparaginaseor dietary asparagine restriction, which limit tumor asparagine consumption, effectivelyimpairs tumor growth in multiple mouse models of cancer. Because environmental asparagineis sufficient to restore tumor growth in the context of respiration impairment, ourfindings suggest that asparagine synthesis is a fundamental purpose of tumor mitochondrialrespiration, which can be harnessed for therapeutic benefit to cancer patients.

DOI: 10.1016/j.cmet.2021.02.001

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00057-7