TY - JOUR TI - Cellular acidosis triggers human MondoA transcriptional activity by driving mitochondrial ATP production AU - Wilde, Blake R AU - Ye, Zhizhou AU - Lim, Tian-Yeh AU - Ayer, Donald E A2 - Cooper, Jonathan A A2 - Jones, Katherine A A2 - Dang, Chi Van VL - 8 PY - 2019 DA - 2019/02/05 SP - e40199 C1 - eLife 2019;8:e40199 DO - 10.7554/eLife.40199 UR - https://doi.org/10.7554/eLife.40199 AB - 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. KW - MondoA KW - TXNIP KW - glucose KW - mitochondrial ATP KW - hexokinase KW - acidosis JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -