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MondoA-Mlx Heterodimers Are Candidate Sensors of Cellular Energy Status: Mitochondrial Localization and Direct Regulation of Glycolysis

Mol. Cell. Biol., 1 July 2006
Vol. 26, Issue 13, p. 4863-4871
DOI: 10.1128/MCB.00657-05

MondoA-Mlx Heterodimers Are Candidate Sensors of Cellular Energy Status: Mitochondrial Localization and Direct Regulation of Glycolysis

  1. Christopher L. Sans,
  2. Daniel J. Satterwhite,
  3. Carrie A. Stoltzman,
  4. Kevin T. Breen and
  5. Donald E. Ayer*
  1. Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, Utah 84112-5550

ABSTRACT

Transcription factors can be sequestered at specific organelles and translocate to the nucleus in response to changes in organellar homeostasis. MondoA is a basic helix-loop-helix leucine zipper transcriptional activator similar to Myc in function. However, unlike Myc, MondoA and its binding partner Mlx localize to the cytoplasm, suggesting tight regulation of their nuclear function. We show here that endogenous MondoA and Mlx associate with mitochondria in primary skeletal muscle cells and erythroblast K562 cells. Interaction between MondoA and the mitochondria is salt and protease sensitive, demonstrating that it associates with the outer mitochondrial membrane by binding a protein partner. Further, endogenous MondoA shuttles between the mitochondria and the nucleus, suggesting that it communicates between these two organelles. When nuclear, MondoA activates transcription of a broad spectrum of metabolic genes, including those for the glycolytic enzymes lactate dehydrogenase A, hexokinase II, and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3. Regulation of these three targets is mediated by direct interaction with CACGTG sites in their promoters. Consistent with its regulation of glycolytic targets, MondoA is both necessary and sufficient for glycolysis. We propose that MondoA communicates information about the intracellular energy state between the mitochondria and the nucleus, resulting in transcriptional activation of glycolytic target genes.

FOOTNOTES

    • Received 12 April 2005.
    • Returned for modification 17 June 2005.
    • Accepted 18 April 2006.
  • *Corresponding author. Mailing address: Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Room 4365, Salt Lake City, UT 84112-5550. Phone: (801) 581-5597. Fax: (801) 585-6410. E-mail: don.ayer{at}hci.utah.edu.
  • Present address: Section of Neonatology, Department of Pediatrics, University of Colorado Denver and Health Sciences Center and The Children's Hospital, Denver, CO 80218.

  • Supplemental material for this article may be found at http://mcb.asm.org/.

Citation:

C. L. Sans, D. J. Satterwhite, C. A. Stoltzman, K. T. Breen, and D. E. Ayer, MondoA-Mlx Heterodimers Are Candidate Sensors of Cellular Energy Status: Mitochondrial Localization and Direct Regulation of Glycolysis. Mol. Cell. Biol. 26, 4863-4871 (2006).

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