| Description |
Transcription factors can be sequestered at specific organelles and translocate to the nucleus only in response to specific extra- or intracellular signals or changes in organellar homeostasis, a process known as retrograde communication. Retrograde communication is becoming a developing signaling paradigm and, in several cases, specific transcription factors associate with organelles and translocate to the nucleus to communicate information about the functional state of the organelle. Subsequently, transcriptional activation or repression typically establishes adaptive positive or negative regulatory feedback circuits, resulting in maintenance of cellular 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 have shown that endogenous MondoA and Mlx associate with the outer mitochondrial membrane through interactions with a protein partner. This association is dynamic, as MondoA shuttles between the mitochondria and the nucleus in a leptomycin B-sensitive fashion, suggesting that it may communicate information between these two organelles. When nuclear, MondoA is capable of activating the transcription of a broad spectrum of metabolic genes, including the glycolytic enzymes lactate dehydrogenase A, hexokinase II, and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3. MondoA directly regulates these genes through interactions with CACGTG E-box consensus sites in their promoters. Consistent with a role for MondoA in regulating glycolysis, upregulated. MondoA increases the glycolytic rate of cells, and MondoA is both necessary and sufficient to drive glycolysis in normal cells. 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. We have found that levels of MondoA are controlled by oncogenic Ras in the BJ fibroblast model of tumorigenesis and that oncogenic Ras increases glycolysis in these cells. In the Ras-transformed cells, MondoA directly activates key glycolytic enzymes that have been implicated in contributing to altered metabolism and aerobic glycolysis during cellular transformation, a process known as the 'Warburg effect'. Taken together, we propose that MondoA upregulation by oncogenic Ras contributes to the increased glycolytic rate observed in this model and that MondoA may be an important transcriptional effector in the metabolic switch to aerobic glycolysis during cellular transformation.. |
