Affiliation:
1. Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
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.
Funder
National Institutes of Health
U.S. Department of Defense
Huntsman Cancer Foundation
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Cited by
41 articles.
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