MondoA senses adenine nucleotides: transcriptional induction of thioredoxin-interacting protein

Abstract

The MondoA–Mlx transcription complex plays a pivotal role in glucose homoeostasis by activating target gene expression in response to G6P (glucose 6-phosphate), the first reaction intermediate in glycolysis. TXNIP (thioredoxin-interacting protein) is a direct and glucose-responsive target of MondoA that triggers a negative-feedback loop by restricting glucose uptake when G6P levels increase. We show in the present study that TXNIP expression is also activated by AICAR (5-amino-4-imidazolecarboxamide ribofuranoside) and adenosine. Using pharmacological inhibitors and genetic knockdowns of purine metabolic enzymes, we establish that TXNIP induction by AICAR and adenosine requires their cellular uptake and metabolism to adenine nucleotides. AICAR induction of TXNIP depended on MondoA, but was independent of AMPK (AMP-activated protein kinase) activation and calcium. The findings of the present study have two important implications. First, in addition to activating AMPK, AICAR may have AMPK-independent effects on gene expression by regulating MondoA–Mlx activity following its flux into the adenine nucleotide pool. Secondly, MondoA–Mlx complexes sense elevated levels of G6P and adenine nucleotides to trigger a TXNIP-dependent feedback inhibition of glycolysis. We propose that this mechanism serves as a checkpoint to restore metabolic homoeostasis.

Beyond the Warburg Effect: N-Myc Contributes to Metabolic Reprogramming in Cancer Cells

“…Deregulated N-Myc requires MondoA for lipid metabolic reprogramming in Myc-driven tumors (58). MondoA is associated with the outer membrane of mitochondria, where it can sense both glycolytic intermediate metabolites characterized by glucose 6-phosphate and mitochondrial metabolites necessary for glutaminolysis (59,60). Metabolites drive the nuclear localization of MondoA, which activates the transcription of genes related to glucose metabolism (61).…”

Cellular acidosis triggers human MondoA transcriptional activity by driving mitochondrial ATP production

“…TXNIP is among a handful of characterized MondoA targets, yet the full scope of the direct MondoA-transcriptome has not been reported. In addition to being regulated by glucose, a functional electron transport chain (ETC) is also required for MondoA-dependent transcription (Yu et al, 2010; Han and Ayer, 2013), yet the ETC-derived signal remains unknown. It is also unclear how glycolytic and mitochondrial signals converge to regulate MondoA transcriptional activity.…”

Deregulated Myc Requires MondoA/Mlx for Metabolic Reprogramming and Tumorigenesis

“…Mlx heterodimerizes with either MondoA or carbohydrate response element binding protein (ChREBP). MondoA associates with the mitochondrial outer membrane, where it can sense both glycolytic intermediates such as glucose 6-phosphate and mitochondrial metabolites (Han and Ayer, 2013; Kaadige et al, 2009; Sloan and Ayer, 2010). Metabolites promote nuclear localization of cytoplasmic MondoA protein, activating transcription of genes involved in glucose metabolism.…”