title: MondoA-Mlx heterodimers are candidate sensors of cellular energy status: mitochondrial localization and direct regulation of glycolysis.
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.
authors.affiliation: Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Room 4365, Salt Lake City, UT 84112-5550, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Sans
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Satterwhite
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Stoltzman
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Breen
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ayer
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000032:analysis / Q000378:metabolism*; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D004734:Energy Metabolism / Q000235:genetics; D004798:Enzymes / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D006019:Glycolysis / Q000235:genetics*; D006801:Humans; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000737:chemistry / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000032:analysis / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004798:Enzymes; C403128:MLX protein, human; C485496:MLXIP protein, human; D024101:Mitochondrial Proteins