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.Retrograde communication between intracellular organelles and the nucleus is a developing signaling paradigm. In several cases, specific transcription factors are associated with organelles and translocate to the nucleus to communicate information about the functional state of the organelle.

Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization

“…MLX interacting protein (MLXIP) in SM and major histocompatibility complex class II DR beta 1 (HLA-DRB1) in AT had gene expression signatures that predict insulin sensitization by TZDs. MLXIP is a transcription factor that activates glycolytic genes (including HK2) in SM (21). Pre-TZD, postclamp SM expression of MLXIP correlated with fractional R d change (r ϭ 0.51) (Fig.…”

“…This may be due to their higher pre-TZD expression level of MLXIP which was predictive of post-TZD insulin sensitization. MLXIP is a metabolic sensor that shuttles between mitochondria and the nucleus where it is a transcription factor activating HK2 and other glycolytic target genes (21). In adipose tissue, pre-TZD HLA-DRB1 expression was correlated with improved insulin sensitivity after TZD treatment.…”

MondoA Senses Non-glucose Sugars

“…Western Blotting-Primary antibodies were used at the following dilutions: anti-MondoA 1:500 (20); anti-VDUP1 (TXNIP) 1:1,000 (Medical and Biological Laboratories); antitubulin 1:10,000 (Sigma). Secondary antibodies were used at 1:5,000 (Amersham Biosciences).…”

Coordination of Nutrient Availability and Utilization by MAX- and MLX-Centered Transcription Networks

“…100 aa, 100 amino acids. (Sans et al 2006), providing an initial subcellular localization regulatory step. Given the multifaceted role played by mitochondria in bioenergetics, we initially postulated that MondoA:MLX complexes sense some aspect of intracellular energy status and communicate that information to the nucleus to trigger an adaptive transcriptional response.…”

“…MondoA is also a bHLHZip factor and like MYC, MondoA has important functions in cell metabolism. Rather than controlling nutrient utilization directly like MYC, MondoA appears to function primarily in how cells sense, respond to, and coordinate the utilization of glucose and glutamine (Sans et al 2006;Stoltzman et al 2008Stoltzman et al , 2011Kaadige et al 2009;Peterson et al 2010;Peterson and Ayer 2011;Havula and Hietakangas 2012). At present, our understanding of the functional interactions between MYC and MondoA is limited.…”