| Description |
The MondoA/TXNIP axis controls glucose homeostasis. The transcription factor MondoA senses glucose-6-phosphate (G6P) and responds by driving expression of thioredoxin-interacting protein (TXNIP), a negative regulator of glucose uptake. The transcriptional activity of MondoA requires oxidative phosphorylation, yet the mechanism is unknown. We studied nutrient sensing by MondoA in the context of acidosis treatment and protein synthesis inhibition, both of which drive MondoA transcriptional activity and TXNIP expression. Both acidosis and protein synthesis inhibition converge on increased synthesis of mitochondrial-ATP (mtATP). Intracellular acidification leads to mitochondrial hyperpolarization and mtATP production through the ATP synthase. Protein synthesis inhibitors also drive mtATP production, likely through increased TCA cycle flux. As mtATP is exported from the mitochondria, it is consumed by mitochondria-bound hexokinase in a reaction that produces G6P. The localized production of G6P drives MondoA transcriptional activity. Thus, by simultaneously sensing glucose and mtATP via production of G6P, MondoA acts as a coincidence detector of the cells primary energy sources. We further show that MondoA drives an adaptive transcriptional response to intracellular acidification and protein synthesis inhibition, of which increased TXNIP is a predominant feature. By characterizing the transcriptional consequences of MondoA and TXNIP loss, we show that TXNIP supports MondoA-dependent transcription. Because TXNIP loss causes a shift away from oxidative metabolism toward aerobic glycolysis, we propose that loss of TXNIP leads to decreased mtATP production, thus restricting MondoA transcriptional activity. Finally, MondoA loss sensitizes cells to Myc-driven cell death. Together these findings further our knowledge of 1) metabolic rewiring during acidosis treatment and protein synthesis inhibition, 2) mtATP and glucose sensing by MondoA, and 3) the biological impacts of MondoA transcriptional activity. Thus, we propose that the MondoA/TXNIP axis is a fundamental attribute of central carbon metabolism and homeostasis. |
