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CELL BIOLOGY
Glucose sensing by MondoA:Mlx complexes: A role for hexokinases and direct regulation of thioredoxin-interacting protein expression

Carrie A. Stoltzman^*, Christopher W. Peterson^*, Kevin T. Breen^*, Deborah M. Muoio, Andrew N. Billin, and Donald E. Ayer^*,

*Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112-5550; Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27704; and Molecular Discovery Research, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709

Edited by Robert N. Eisenman, Fred Hutchinson Cancer Research Center, Seattle, WA, and approved March 13, 2008 (received for review December 24, 2007)

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.

metabolism | mitochondria | transcription

Author contributions: C.A.S. and C.W.P. contributed equally to this work; C.A.S., C.W.P., D.M.M., A.N.B., and D.E.A. designed research; C.A.S., C.W.P., and K.T.B. performed research; D.M.M., A.N.B., and D.E.A. analyzed data; and C.A.S., C.W.P., and D.E.A. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

To whom correspondence should be addressed. E-mail: don.ayer{at}hci.utah.edu

© 2008 by The National Academy of Sciences of the USA

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