Cellular acidosis triggers human MondoA transcriptional activity by driving mitochondrial ATP production
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 05, 2019
- Source ID
- 10.7554/elife.40199
Entities
People
- Blake R Wilde
- Donald E Ayer
- Tian-yeh Lim
- Zhizhou Ye
Organizations
- National Institutes of Health
- United States Department of Defense
- University of Utah