Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States.
Elife. 2019 Feb 5;8:e40199. doi: 10.7554/eLife.40199.
Human MondoA requires glucose as well as other modulatory signals to function in transcription. One such signal is acidosis, which increases MondoA activity and also drives a protective gene signature in breast cancer. How low pH controls MondoA transcriptional activity is unknown. We found that low pH medium increases mitochondrial ATP (mtATP), which is subsequently exported from the mitochondrial matrix. Mitochondria-bound hexokinase transfers a phosphate from mtATP to cytoplasmic glucose to generate glucose-6-phosphate (G6P), which is an established MondoA activator. The outer mitochondrial membrane localization of MondoA suggests that it is positioned to coordinate the adaptive transcriptional response to a cell's most abundant energy sources, cytoplasmic glucose and mtATP. In response to acidosis, MondoA shows preferential binding to just two targets, TXNIP and its paralog ARRDC4. Because these transcriptional targets are suppressors of glucose uptake, we propose that MondoA is critical for restoring metabolic homeostasis in response to high energy charge.
人类 MondoA 在转录中需要葡萄糖和其他调节信号才能发挥作用。其中一个信号是酸中毒，它可以增加 MondoA 的活性，并在乳腺癌中驱动保护性基因特征。低 pH 值如何控制 MondoA 的转录活性尚不清楚。我们发现，低 pH 值培养基会增加线粒体 ATP（mtATP），随后 mtATP 从线粒体基质中输出。线粒体结合的己糖激酶将 mtATP 上的一个磷酸基团转移到细胞质葡萄糖上，生成葡萄糖-6-磷酸（G6P），这是一种已被证实的 MondoA 激活剂。MondoA 的定位于线粒体的外部表明它可以协调细胞对最丰富的能量来源，即细胞质葡萄糖和 mtATP 的适应性转录反应。在酸中毒的情况下，MondoA 显示出对仅两个靶标的优先结合，即 TXNIP 和其同源物 ARRDC4。因为这些转录靶标是葡萄糖摄取的抑制剂，所以我们提出 MondoA 对于恢复高能荷下的代谢平衡至关重要。
