Glucose sensing by MondoA:Mlx complexes: A role for hexokinases and direct regulation of thioredoxin-interacting protein expression
- 13 May 2008
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 105 (19), 6912-6917
- https://doi.org/10.1073/pnas.0712199105
Abstract
Glucose is a fundamental metabolite, yet how cells sense and respond to changes in extracellular glucose concentration is not completely understood. We recently reported that the MondoA:Mlx dimeric transcription factor directly regulates glycolysis. In this article, we consider whether MondoA:Mlx complexes have a broader role in sensing and responding to glucose status. In their latent state, MondoA:Mlx complexes localize to the outer mitochondrial membrane, yet shuttle between the mitochondria and the nucleus. We show that MondoA:Mlx complexes accumulate in the nucleus in response to glucose and 2-deoxyglucose (2-DG). Furthermore, nuclear localization of MondoA:Mlx depends on the enzymatic activity of hexokinases. These enzymes catalyze conversion of glucose to glucose-6-phosphate (G6P), which is the first step in the glycolytic pathway. Together, these findings suggest that MondoA:Mlx monitors intracellular G6P concentration and translocates to the nucleus when levels of this key metabolite increase. Transcriptional profiling experiments demonstrate that MondoA is required for >75% of the 2-DG-induced transcription signature. We identify thioredoxin-interacting protein (TXNIP) as a direct and glucose-regulated MondoA:Mlx transcriptional target. Furthermore, MondoA:Mlx complexes, via their regulation of TXNIP, are potent negative regulators of glucose uptake. These studies suggest a key role for MondoA:Mlx complexes in the adaptive transcriptional response to changes in extracellular glucose concentration and peripheral glucose uptake.Keywords
This publication has 27 references indexed in Scilit:
- TXNIP Regulates Peripheral Glucose Metabolism in HumansPLoS Medicine, 2007
- Energy sensing and regulation of gene expression in skeletal muscleJournal of Applied Physiology, 2007
- Regulatory Functions of Nuclear Hexokinase1 Complex in Glucose SignalingCell, 2006
- Vitamin D3upregulated protein 1 (VDUP1) is a regulator for redox signaling and stress-mediated diseasesThe Journal of Dermatology, 2006
- Hexokinase II: Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondriaOncogene, 2006
- The Interaction of Thioredoxin with TxnipJournal of Biological Chemistry, 2006
- Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmonyJCI Insight, 2006
- MondoA-Mlx Heterodimers Are Candidate Sensors of Cellular Energy Status: Mitochondrial Localization and Direct Regulation of GlycolysisMolecular and Cellular Biology, 2006
- Probing tumor phenotypes using stable and regulated synthetic microRNA precursorsNature Genetics, 2005
- A Novel Heterodimerization Domain, CRM1, and 14-3-3 Control Subcellular Localization of the MondoA-Mlx HeterocomplexMolecular and Cellular Biology, 2002