Affinage

MLXIP

MLX-interacting protein · UniProt Q9HAP2

Length
919 aa
Mass
101.2 kDa
Annotated
2026-06-10
36 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MLXIP (MondoA) is a basic helix-loop-helix-leucine zipper transcription factor that serves as a central cellular nutrient sensor, transducing metabolic state into transcriptional programs that restrain glucose uptake and glycolysis (PMID:11073985, PMID:16782875). It functions as an obligate heterocomplex with Mlx, which it preferentially dimerizes with over Max/Myc/Mad partners; dimerization occurs through a C-terminal interface distinct from the leucine zipper and inactivates cytoplasmic-retention activity (PMID:11073985, PMID:12446771). In the resting state the complex is held in the cytoplasm and at the outer mitochondrial membrane through two N-terminal Mondo conserved regions, MCR II acting as a CRM1-dependent nuclear export signal and MCR III binding 14-3-3 proteins (PMID:12446771, PMID:16782875). Nutrient signals drive nuclear accumulation and activation in sequential steps—nuclear entry, target-promoter occupancy at CACGTG E-boxes, and recruitment of a histone H3 acetyltransferase—each requiring sustained glucose signaling (PMID:20385767). The proximal activating metabolite is glucose-6-phosphate generated by mitochondria-bound hexokinase using mitochondrial ATP, engaging MondoA via residues GKL139-141; the complex also senses other hexose phosphates and adenine nucleotides, while glutamine/TCA anaplerosis recruits an HDAC corepressor to antagonize activation (PMID:30717828, PMID:31993438, PMID:19706488, PMID:23631812). Through this circuitry MondoA directly drives transcription of glycolytic genes (LDHA, HKII, PFKFB3) and, most prominently, the feedback inhibitors TXNIP and ARRDC4, creating a negative loop that limits glucose uptake and is also responsive to lactic acidosis via SENP1-dependent deSUMOylation and antagonized by mTOR binding and MEK1-mediated Tyr222 phosphorylation (PMID:16782875, PMID:20844768, PMID:25332233, PMID:36398713, PMID:40846790). MondoA is co-opted by oncogenic MYC for metabolic reprogramming and tumor cell survival across multiple cancers, and in MYC-amplified pancreatic cancer it sustains viability by coordinating the MYC network with the Integrated Stress Response through ATF4 translation (PMID:25640402, PMID:41779777). In vivo, MondoA controls fuel selection, skeletal muscle glycogen and myogenesis, β-cell and T-cell glucose handling, and renal autophagy (PMID:25145386, PMID:32431117, PMID:29282201, PMID:40846790, PMID:38819935).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2000 High

    Established the molecular identity of MondoA as a bHLH-zip factor that signals through an Mlx heterocomplex rather than the Myc/Max/Mad network, and that its activity is gated by nucleocytoplasmic shuttling.

    Evidence Co-IP, leptomycin B nuclear export inhibition, and domain mapping with heterologous NLS reporters

    PMID:11073985

    Open questions at the time
    • Did not identify the activating signal driving nuclear entry
    • No endogenous target genes defined
  2. 2002 High

    Defined the architecture of cytoplasmic retention, showing that a non-zipper C-terminal interface mediates heterodimerization while N-terminal MCRs enforce CRM1- and 14-3-3-dependent retention requiring an external signal to overcome.

    Evidence Domain deletion/mutagenesis, co-IP, CRM1 inhibition, and 14-3-3 binding assays

    PMID:12446771

    Open questions at the time
    • The extracellular/metabolic signal overriding retention was not identified
    • 14-3-3 recruitment regulation undefined
  3. 2006 High

    Localized the resting complex to the outer mitochondrial membrane and demonstrated MondoA is both necessary and sufficient for glycolysis by directly activating glycolytic gene promoters.

    Evidence Subcellular fractionation with salt/protease controls, ChIP, and loss/gain-of-function glycolysis assays in muscle and erythroblast cells

    PMID:16782875

    Open questions at the time
    • Identity of the mitochondrial tethering partner unknown
    • Did not link mitochondrial signal to nuclear activation
  4. 2009 High

    Placed MondoA upstream of TXNIP in a glucose-uptake feedback loop and showed glutamine anaplerosis antagonizes it via HDAC corepressor recruitment.

    Evidence Reporter assays, HDAC inhibition, alpha-ketoglutarate supplementation, and knockdown with glucose uptake measurement

    PMID:19706488

    Open questions at the time
    • Identity of the HDAC-dependent corepressor not defined
    • Direct glucose-derived activating metabolite still unknown at this stage
  5. 2010 High

    Dissected glucose control into three sequential steps and showed nuclear localization alone is insufficient without continued signaling for HAT recruitment.

    Evidence ChIP, chromatin fractionation, glucose dose-response, and HAT recruitment assays

    PMID:20385767

    Open questions at the time
    • Identity of the specific H3 acetyltransferase not pinned down
    • Molecular sensor of glucose signal still unresolved
  6. 2010 Medium

    Showed the complex paradoxically responds to lactic acidosis like glucose to induce TXNIP/ARRDC4 and curb tumor glycolysis.

    Evidence Transcriptome comparison and MondoA:Mlx functional assays under lactic acidosis

    PMID:20844768

    Open questions at the time
    • Mechanistic pathway placement relied on indirect evidence
    • Molecular link between acidosis and complex activation not established
  7. 2011 High

    Broadened the sensing repertoire to non-glucose hexoses and their 6-phosphates, narrowing the activating signal toward hexose-phosphate metabolites.

    Evidence Nuclear accumulation and TXNIP assays with metabolic inhibitors in MondoA-null and TXNIP-null MEFs

    PMID:21908621

    Open questions at the time
    • Direct binding of the phosphorylated hexose to MondoA not yet shown
    • Binding site unmapped
  8. 2013 Medium

    Demonstrated MondoA additionally senses adenine nucleotides independently of AMPK and calcium, indicating multi-metabolite integration.

    Evidence TXNIP expression with purine-metabolism inhibitors, enzyme knockdowns, and AMPK/calcium pathway inhibition

    PMID:23631812

    Open questions at the time
    • Whether adenine nucleotides bind MondoA directly not shown
    • Single-lab study
  9. 2014 Medium

    Identified mTOR as a cytoplasmic MondoA-binding antagonist that blocks complex formation, and established a reciprocal MondoA-TXNIP suppression of mTORC1.

    Evidence Reciprocal co-IP, mTOR inhibitor and ROS treatment, complex-formation and TXNIP assays

    PMID:25332233

    Open questions at the time
    • Structural basis of mTOR-MondoA interaction undefined
    • Single-lab study
  10. 2014 Medium

    Revealed an in vivo role in fuel selection: MondoA represses PGC-1α-driven PDK4 transcription, directing pyruvate fate.

    Evidence MondoA-/- mice with exercise testing, promoter analysis, and metabolite measurement

    PMID:25145386

    Open questions at the time
    • Mechanism of PGC-1α/PDK4 repression not detailed
    • Single-lab study
  11. 2015 High

    Established that oncogenic Myc depends on MondoA:Mlx for metabolic reprogramming and tumor survival, defining a co-regulated metabolic gene set.

    Evidence MondoA/Mlx knockdown in Myc-overexpressing cells with NMR metabolomics and apoptosis assays

    PMID:25640402

    Open questions at the time
    • Direct co-occupancy mechanism with Myc not fully resolved at this stage
    • Therapeutic targetability not yet shown
  12. 2016 High

    Provided a druggable handle: the small molecule SBI-477 deactivates MondoA, lowers TXNIP/ARRDC4, enhances glucose uptake, and improves glucose tolerance in vivo.

    Evidence Chemical screen, MondoA knockdown, expression and glucose uptake assays, and high-fat-diet mouse testing

    PMID:27500491

    Open questions at the time
    • Direct molecular target/binding mode of SBI-477 on MondoA not defined
    • Tissue selectivity not established
  13. 2017 Medium

    Showed MondoA, not ChREBP, is the dominant glucose-responsive factor in human β-cells, with cAMP signaling suppressing its nuclear shuttling.

    Evidence Knockdown, nuclear translocation and TXNIP/ARRDC4 assays with cAMP agonists in human islets and EndoC-βH1

    PMID:29282201

    Open questions at the time
    • Mechanism by which cAMP blocks shuttling unclear
    • Single-lab study
  14. 2019 High

    Unified mitochondrial localization with metabolite sensing: acidosis raises mtATP, which mitochondria-bound hexokinase uses to generate G6P that activates MondoA at TXNIP/ARRDC4 promoters.

    Evidence mtATP and G6P measurement, hexokinase/VDAC inhibition, localization and ChIP assays under acidosis

    PMID:30717828

    Open questions at the time
    • Direct G6P-MondoA binding not yet demonstrated here
    • How acidosis raises mtATP mechanistically incomplete
  15. 2020 Medium

    Confirmed G6P as the direct activating ligand and mapped GKL139-141 as the binding residues.

    Evidence Knockdown, EMSA, site-directed mutagenesis, and molecular docking

    PMID:31993438

    Open questions at the time
    • In silico docking does not independently confirm binding geometry
    • No high-resolution structure of the G6P-bound complex
  16. 2020 Medium

    Extended in vivo function to myogenesis and muscle glycogen control, linking MondoA loss to PTEN/PI3K/Akt signaling and TXNIP-GLUT4-driven glucose uptake.

    Evidence Muscle-specific knockout mice, C2C12 knockdown, functional myoblast assays, and glycogen/GLUT4 measurement

    PMID:32431117

    Open questions at the time
    • Direct versus indirect regulation of PTEN/PI3K/Akt unclear
    • Single-lab study
  17. 2020 Medium

    Showed protein synthesis inhibitors activate MondoA-dependent TXNIP via mtATP/G6P generation requiring VDAC-hexokinase coupling and the electron transport chain, contributing to drug cytotoxicity.

    Evidence RNA-seq, metabolomics, knockdown, VDAC/HK inhibition, and cytotoxicity assays in cell lines and PDxO

    PMID:33292639

    Open questions at the time
    • How translation inhibition raises mtATP not fully resolved
    • Single-lab study
  18. 2022 Medium

    Identified MEK1 as a direct binding partner that phosphorylates MondoA at Tyr222 to block nuclear translocation, with ketone bodies activating MondoA by disrupting this interaction.

    Evidence Co-IP/MS, MEK1 knockdown, Y222 mutagenesis, translocation and TXNIP reporter assays

    PMID:36398713

    Open questions at the time
    • Whether MEK1 phosphorylates Y222 directly versus via intermediary kinase not fully resolved
    • Single-lab study
  19. 2022 Medium

    Showed MondoA restricts oxidative phosphorylation by limiting pyruvate dehydrogenase activity, supporting B-ALL transformation.

    Evidence CRISPR and RNAi knockdown, TCA/OXPHOS metabolic analysis, and in vivo model with patient dataset correlation

    PMID:33908607

    Open questions at the time
    • Transcriptional targets mediating PDH restriction not fully mapped
    • Single-lab study
  20. 2023 Medium

    Revealed a non-canonical role: PRMT1 recruits MLXIP to the β-catenin promoter to activate β-catenin signaling in gastric cancer.

    Evidence Co-IP/pulldown and ChIP with PRMT1 knockdown/inhibition functional assays

    PMID:37554218

    Open questions at the time
    • Whether this is Mlx-dependent or E-box-mediated unclear
    • Single co-IP plus ChIP without reciprocal mechanistic depth
  21. 2024 High

    Defined the MondoA-TXNIP axis as an immunometabolic brake: SENP1-dependent activation under lactic acid restrains T-cell glucose uptake, shaping Treg suppression and CD8+ cytotoxicity.

    Evidence Cell-type-specific knockouts, TXNIP and SENP1 assays, glucose/glycolysis measurement, cytotoxicity and anti-PD-1 tumor models

    PMID:40846790

    Open questions at the time
    • How SENP1 deSUMOylation activates MondoA mechanistically not fully detailed
    • SUMO acceptor site on MondoA not defined here
  22. 2024 Medium

    Showed renal MondoA suppresses Rubicon to permit autophagy and drives TFEB-PGC-1α-dependent mitochondrial biogenesis, protecting against acute kidney injury.

    Evidence Proximal-tubule-specific knockout with Rubicon ablation epistasis, autophagy and TFEB/PGC-1α assays

    PMID:38819935

    Open questions at the time
    • Whether Rubicon and TFEB/PGC-1α are direct MondoA transcriptional targets unclear
    • Single-lab study
  23. 2025 High

    Established a mechanistic link between MondoA, deregulated MYC, and the Integrated Stress Response, with MondoA sustaining ATF4 translation in MYC-amplified PDAC.

    Evidence CRISPR knockout, ChIP-seq, m6A profiling, ATF4 rescue, and small-molecule inhibition in PDAC cells and organoids

    PMID:41779777

    Open questions at the time
    • How MondoA controls m6A and ATF4 translation mechanistically not resolved
    • Identity of small-molecule target site unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of metabolite (G6P/adenine nucleotide) binding, the identity of the mitochondrial tethering partner, and the molecular mechanism linking SUMOylation/phosphorylation states to MondoA shuttling remain unresolved.
  • No experimental high-resolution structure of MondoA or its metabolite-bound state
  • Mitochondrial outer-membrane receptor for MondoA unidentified
  • Direct HAT and HDAC corepressor identities undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0140110 transcription regulator activity 3 GO:0140299 molecular sensor activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 1
Partners
MAP2K1MLXMTORPRMT1SENP1
Complex memberships
MondoA:Mlx heterocomplex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 MondoA is a bHLH-leucine zipper transcription factor that preferentially forms heterodimers with Mlx (not Max, Myc, or Mad family members); the MondoA:Mlx heterocomplex localizes primarily to the cytoplasm but shuttles to the nucleus (blocked by leptomycin B nuclear export inhibitor), and when nuclear it binds CACGTG E-boxes and activates transcription. The amino terminus of MondoA contains separable cytoplasmic localization and transcription activation domains. Co-IP (in vivo association), leptomycin B treatment, reporter assays with heterologous NLS, deletion/domain mapping Molecular and cellular biology High 11073985
2002 The C-terminal domain shared by MondoA and Mlx functions as a novel dimerization interface (independent of the leucine zipper) that mediates heterotypic MondoA:Mlx interactions; this dimerization inactivates the cytoplasmic localization activity of their C termini. Two N-terminal Mondo conserved regions (MCRs) retain the heterocomplex in the cytoplasm: MCR II acts as a CRM1-dependent nuclear export signal, and MCR III is a binding site for 14-3-3 family members. Nuclear accumulation requires both heterodimerization and an extracellular signal overcoming CRM1/14-3-3-mediated cytoplasmic retention. Domain deletion/mutagenesis, co-IP, subcellular localization assays, CRM1 inhibitor (leptomycin B), 14-3-3 binding assays Molecular and cellular biology High 12446771
2006 Endogenous MondoA and Mlx associate with the outer mitochondrial membrane (interaction is salt- and protease-sensitive, indicating binding to a protein partner) in primary skeletal muscle cells and K562 erythroblasts. MondoA shuttles between mitochondria and nucleus. When nuclear, MondoA directly activates transcription of glycolytic genes (LDHA, HKII, PFKFB3) via CACGTG sites in their promoters, and MondoA is both necessary and sufficient for glycolysis. Subcellular fractionation, salt/protease sensitivity assays, ChIP, reporter assays, knockdown/overexpression functional glycolysis assays Molecular and cellular biology High 16782875
2009 Glutamine inhibits MondoA:Mlx-dependent transcriptional activation of TXNIP by triggering recruitment of a histone deacetylase (HDAC)-dependent corepressor to the amino terminus of MondoA. A cell-permeable TCA cycle intermediate, alpha-ketoglutarate, mimics this effect, indicating glutamine acts through mitochondrial anaplerosis. MondoA knockdown reduces TXNIP expression and elevates glucose uptake, placing MondoA upstream of TXNIP in the glucose-uptake feedback loop. Reporter assays, HDAC inhibitor treatment, alpha-ketoglutarate supplementation, MondoA knockdown with glucose uptake measurement Proceedings of the National Academy of Sciences of the United States of America High 19706488
2010 Glucose controls MondoA:Mlx activity at three sequential steps: (1) nuclear accumulation, (2) promoter occupancy at target genes, and (3) recruitment of a histone H3 acetyltransferase to promoter-bound MondoA:Mlx to activate transcription. Simply achieving nuclear localization is insufficient for transcriptional activation without continued glucose signaling. ChIP, reporter assays, glucose dose-response experiments, chromatin fractionation, HAT recruitment assays Molecular and cellular biology High 20385767
2010 Lactic acidosis activates the MondoA:Mlx glucose-sensing complex to induce TXNIP and ARRDC4 transcription (paradoxically similar to glucose exposure rather than glucose deprivation), contributing to inhibition of tumor glycolysis. This was demonstrated by showing that MondoA:Mlx activation mediates the lactic acidosis transcriptional response. Global transcriptome comparison, MondoA:Mlx functional assays, glucose uptake measurements under lactic acidosis PLoS genetics Medium 20844768
2011 MondoA:Mlx senses non-glucose hexoses (allose, 3-O-methylglucose, glucosamine) in addition to glucose, accumulating in the nucleus and activating TXNIP transcription. MondoA can sense glucosamine-6-phosphate in addition to glucose-6-phosphate. The MondoA-TXNIP regulatory circuit contributes to the hexose transport curb, demonstrated using MondoA-null and TXNIP-null MEFs. Nuclear accumulation assays, TXNIP reporter/expression assays with metabolic inhibitors, MondoA-null and TXNIP-null MEF glucose uptake measurements The Journal of biological chemistry High 21908621
2012 In hepatocytes, MondoA (not ChREBP) is required for glucose-induced transcription of PTG (protein targeting to glycogen), an effect dependent on fructose 2,6-bisphosphate. Elevated fructose 2,6-bisphosphate is essential for MondoA nuclear translocation and recruitment to the PTG promoter; depletion of fructose 2,6-bisphosphate prevents this. ChIP, MondoA/ChREBP knockdown, forced elevation/depletion of fructose 2,6-bisphosphate, nuclear translocation assays Molecular and cellular biology Medium 23207906
2013 MondoA:Mlx complexes sense adenine nucleotides: TXNIP expression is activated by AICAR and adenosine through their cellular uptake and metabolism to adenine nucleotides. This induction is MondoA-dependent but AMPK-independent and calcium-independent, revealing that MondoA senses both glucose-6-phosphate and adenine nucleotides to trigger TXNIP-dependent feedback inhibition of glycolysis. TXNIP expression assays, pharmacological inhibitors of purine metabolism, genetic knockdowns of purine metabolic enzymes, AMPK/calcium pathway inhibition The Biochemical journal Medium 23631812
2014 mTOR binds to MondoA in the cytoplasm and prevents MondoA:Mlx complex formation, restricting MondoA's nuclear entry and reducing TXNIP expression. Conversely, MondoA can suppress mTORC1 activity via direct transcriptional regulation of TXNIP. mTOR inhibitors and reactive oxygen species (ROS) regulate the MondoA-mTOR interaction in opposing directions. Co-IP (mTOR-MondoA interaction), mTOR inhibitor treatment, ROS treatment, TXNIP reporter/expression assays, MondoA-Mlx complex formation assays Molecular and cellular biology Medium 25332233
2014 MondoA-knockout mice show enhanced glycolytic capacity and excel in sprinting. MondoA functionally represses PGC-1α-mediated activation of PDK4 (pyruvate dehydrogenase kinase 4) transcription; absence of MondoA diverts pyruvate toward lactate and alanine rather than acetyl-CoA, revealing a role for MondoA in fuel selection in vivo. Gene-targeted MondoA-/- mice, gene expression analysis, promoter analysis, exercise testing, metabolite measurement (lactate, alanine, fatty acids) The Biochemical journal Medium 25145386
2015 Oncogenic Myc requires MondoA and its partner Mlx for metabolic reprogramming and tumorigenesis. Knockdown of MondoA or Mlx blocks Myc-induced reprogramming of multiple metabolic pathways (including lipid biosynthesis) and results in apoptosis. Myc and MondoA co-regulate a set of metabolic genes critical for survival of Myc-driven cancer. MondoA/Mlx knockdown in Myc-overexpressing cells, metabolic profiling (NMR metabolomics), apoptosis assays, co-regulated gene identification and knockdown Cancer cell High 25640402
2016 MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling: deactivation of MondoA by the small molecule SBI-477 reduces expression of TXNIP and ARRDC4, insulin pathway suppressors, and enhances glucose uptake. MondoA depletion in myocytes reproduces these effects, and a SBI-477 analog improved glucose tolerance in high-fat-diet mice. High-throughput chemical screen, MondoA knockdown, TXNIP/ARRDC4 expression measurement, glucose uptake assays, in vivo mouse metabolic testing The Journal of clinical investigation High 27500491
2017 MondoA (not its paralog ChREBP) is the predominant glucose-responsive transcription factor in human pancreatic β-cells (EndoC-βH1 and human islets). Under high glucose, MondoA shuttles to the nucleus and is required for induction of TXNIP and ARRDC4. Increasing cAMP signaling (via forskolin or GLP-1 mimetic Exendin-4) inhibits MondoA nuclear shuttling and suppresses TXNIP/ARRDC4 expression. MondoA silencing improves glucose uptake in β-cells. MondoA knockdown, nuclear translocation assays, cAMP agonist treatment, TXNIP/ARRDC4 expression in human islets and cell lines Diabetes Medium 29282201
2019 Cellular acidosis (low pH) increases MondoA transcriptional activity by driving increased mitochondrial ATP (mtATP) production and export. Mitochondria-bound hexokinase uses mtATP to phosphorylate cytoplasmic glucose, generating glucose-6-phosphate (G6P), which activates MondoA. The outer mitochondrial membrane localization of MondoA positions it to coordinate responses to glucose and mtATP. In response to acidosis, MondoA preferentially binds TXNIP and ARRDC4 promoters. mtATP measurement, hexokinase inhibition, G6P measurement, MondoA localization and ChIP assays, acidosis treatment eLife High 30717828
2020 G6P (glucose-6-phosphate) is the metabolic intermediate that directly activates the MondoA/Mlx heterocomplex to induce Txnip expression, confirmed by endogenous knockdown and EMSA (gel shift). Mutational analysis identified residues GKL139-141 in MondoA as mediating G6P binding, based on molecular docking, binding free energy decomposition, and functional mutagenesis. MondoA knockdown, EMSA (electrophoretic mobility shift assay), site-directed mutagenesis of G6P-binding residues, molecular docking/in silico modeling Frontiers in molecular biosciences Medium 31993438
2020 MondoA is required for normal myogenesis and regulation of skeletal muscle glycogen content. Muscle-specific MondoA knockout (MAKO) causes muscle fiber atrophy and increased glycogen. MondoA knockdown inhibits myoblast proliferation, migration, and differentiation through the PTEN/PI3K/Akt pathway. Increased glycogen in MAKO mice results from TXNIP downregulation leading to GLUT4 upregulation and increased glucose uptake. Muscle-specific MondoA knockout mice, C2C12 siRNA knockdown, myoblast functional assays (proliferation, migration, differentiation), glycogen measurement, TXNIP/GLUT4 expression analysis Diabetes & metabolism journal Medium 32431117
2020 Multiple protein synthesis inhibitors (rocaglamide A, cycloheximide) increase MondoA-dependent TXNIP expression by increasing mitochondrial ATP (mtATP) and G6P levels. This effect depends on interactions between VDAC and hexokinase, which generates G6P, and requires a functional electron transport chain. RocA-driven cytotoxicity is partially dependent on MondoA or TXNIP. RNA-seq, metabolomics, MondoA knockdown, VDAC/HK interaction inhibition, mtATP and G6P measurement, cytotoxicity assays in cell lines and PDxO models Cancer & metabolism Medium 33292639
2022 Ketone bodies promote MondoA nuclear translocation and TXNIP promoter binding. MEK1 physically interacts with MondoA, enhances tyrosine-222 phosphorylation of MondoA, and inhibits MondoA nuclear translocation and transcriptional activity. Ketone bodies reduce glucose uptake by blocking MEK1-MondoA interaction, decreasing MEK1-dependent tyrosine-222 phosphorylation of MondoA, and thereby promoting MondoA nuclear translocation and TXNIP transcription. Proteomic identification of MEK1 as MondoA binding partner (Co-IP/MS), MEK1 knockdown, phosphorylation site mutagenesis (Y222), nuclear translocation assays, TXNIP reporter, glucose uptake assays Cancer science Medium 36398713
2022 MondoA senses metabolic stress in B-ALL cells by restricting oxidative phosphorylation through reduced pyruvate dehydrogenase activity. Loss of MondoA correlates with increased TCA cycle activity. MondoA depletion reduces transformational capacity of B-ALL cells in vitro and dramatically inhibits malignant potential in vivo. CRISPR/Cas9 and RNAi knockdown, metabolic pathway analysis (TCA cycle, OXPHOS), in vivo mouse model, patient dataset correlation Blood Medium 33908607
2023 PRMT1 binds to MLXIP (MondoA) and recruits it to the promoter of β-catenin, inducing β-catenin transcription and activating the β-catenin signaling pathway in gastric cancer cells. PRMT1 and MLXIP were identified as interaction partners by co-IP/pulldown. Co-IP/pulldown (PRMT1-MLXIP interaction), ChIP (MLXIP recruitment to β-catenin promoter), PRMT1 knockdown/inhibition functional assays Genes & diseases Medium 37554218
2024 Lactic acid relies on SENP1 (sentrin/SUMO-specific protease 1) to stimulate the MondoA-TXNIP axis. MondoA-induced TXNIP transcription impairs TCR/CD28-signal-induced CD8+ T cell activation and restricts glucose uptake and glycolysis. MondoA deficiency in Treg cells reduces their immunosuppressive capacity, while MondoA loss in CD8+ T cells enhances cytotoxicity by restoring glucose uptake. MondoA knockout in specific T cell populations, TXNIP expression assays, SENP1 functional assays, glucose uptake/glycolysis measurement, CD8+ T cell cytotoxicity assays, anti-PD-1 combination tumor models Nature metabolism High 40846790
2024 MondoA ablation in proximal tubules increases Rubicon expression and inhibits autophagy, increasing vulnerability to AKI. Ablation of Rubicon in MondoA-deficient kidneys rescues autophagy and protects mitochondrial function. During recovery from ischemia-reperfusion, MondoA promotes TFEB-PGC-1α axis activity to maintain mitochondrial biogenesis. Proximal tubule-specific MondoA knockout mice, Rubicon ablation epistasis, autophagy assays, TFEB/PGC-1α expression analysis, pharmacological TFEB upregulation Journal of the American Society of Nephrology : JASN Medium 38819935
2025 In MYC-amplified PDAC, MondoA is required for viability, facilitating proliferation and suppressing apoptosis. Loss of MondoA shifts genomic occupancy of MYC, MNT, and ChREBP, alters m6A modification of mRNA globally, and disrupts coordination between the MYC network and the Integrated Stress Response (ISR) by decreasing ATF4 mRNA translation. Re-expression of ATF4 rescues diminished viability caused by MondoA loss, establishing a direct mechanistic link between MondoA, deregulated MYC, and the ISR. CRISPR/Cas9 knockdown, transcriptional/genomic profiling (ChIP-seq), m6A profiling, ATF4 rescue experiments, small-molecule MondoA inhibition in PDAC cell lines and patient-derived organoids Proceedings of the National Academy of Sciences of the United States of America High 41779777

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Deregulated Myc requires MondoA/Mlx for metabolic reprogramming and tumorigenesis. Cancer cell 176 25640402
2009 Glutamine-dependent anapleurosis dictates glucose uptake and cell growth by regulating MondoA transcriptional activity. Proceedings of the National Academy of Sciences of the United States of America 140 19706488
2000 MondoA, a novel basic helix-loop-helix-leucine zipper transcriptional activator that constitutes a positive branch of a max-like network. Molecular and cellular biology 112 11073985
2010 Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA. PLoS genetics 108 20844768
2006 MondoA-Mlx heterodimers are candidate sensors of cellular energy status: mitochondrial localization and direct regulation of glycolysis. Molecular and cellular biology 97 16782875
2010 Glucose controls nuclear accumulation, promoter binding, and transcriptional activity of the MondoA-Mlx heterodimer. Molecular and cellular biology 79 20385767
2016 MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling. The Journal of clinical investigation 61 27500491
2011 MondoA senses non-glucose sugars: regulation of thioredoxin-interacting protein (TXNIP) and the hexose transport curb. The Journal of biological chemistry 61 21908621
2015 Interactions between Myc and MondoA transcription factors in metabolism and tumourigenesis. British journal of cancer 52 26469830
2002 A novel heterodimerization domain, CRM1, and 14-3-3 control subcellular localization of the MondoA-Mlx heterocomplex. Molecular and cellular biology 45 12446771
2017 MondoA/ChREBP: The usual suspects of transcriptional glucose sensing; Implication in pathophysiology. Metabolism: clinical and experimental 44 28403938
2019 Cellular acidosis triggers human MondoA transcriptional activity by driving mitochondrial ATP production. eLife 42 30717828
2018 c-Myc-driven glycolysis via TXNIP suppression is dependent on glutaminase-MondoA axis in prostate cancer. Biochemical and biophysical research communications 42 30103944
2017 MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells. Diabetes 35 29282201
2014 MondoA-Mlx transcriptional activity is limited by mTOR-MondoA interaction. Molecular and cellular biology 33 25332233
2012 Glucose induces protein targeting to glycogen in hepatocytes by fructose 2,6-bisphosphate-mediated recruitment of MondoA to the promoter. Molecular and cellular biology 27 23207906
2020 TXNIP induced by MondoA, rather than ChREBP, suppresses cervical cancer cell proliferation, migration and invasion. Journal of biochemistry 23 31782782
2010 Activation and repression of glucose-stimulated ChREBP requires the concerted action of multiple domains within the MondoA conserved region. American journal of physiology. Endocrinology and metabolism 21 20682844
2023 PRMT1 promotes the proliferation and metastasis of gastric cancer cells by recruiting MLXIP for the transcriptional activation of the β-catenin pathway. Genes & diseases 20 37554218
2025 Targeting MondoA-TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment. Nature metabolism 19 40846790
2019 Glucose-Sensing Transcription Factor MondoA/ChREBP as Targets for Type 2 Diabetes: Opportunities and Challenges. International journal of molecular sciences 19 31623194
2012 MondoA is highly overexpressed in acute lymphoblastic leukemia cells and modulates their metabolism, differentiation and survival. Leukemia research 17 22748921
2014 MondoA deficiency enhances sprint performance in mice. The Biochemical journal 15 25145386
2022 MondoA drives malignancy in B-ALL through enhanced adaptation to metabolic stress. Blood 12 33908607
2013 MondoA senses adenine nucleotides: transcriptional induction of thioredoxin-interacting protein. The Biochemical journal 12 23631812
2023 The Function of MondoA and ChREBP Nutrient-Sensing Factors in Metabolic Disease. International journal of molecular sciences 11 37240157
2020 Glucose-6-Phosphate Upregulates Txnip Expression by Interacting With MondoA. Frontiers in molecular biosciences 10 31993438
2020 Protein synthesis inhibitors stimulate MondoA transcriptional activity by driving an accumulation of glucose 6-phosphate. Cancer & metabolism 9 33292639
2024 MondoA and AKI and AKI-to-CKD Transition. Journal of the American Society of Nephrology : JASN 7 38819935
2016 Contrasting Patterns in the Evolution of Vertebrate MLX Interacting Protein (MLXIP) and MLX Interacting Protein-Like (MLXIPL) Genes. PloS one 7 26910886
2024 The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas. EMBO molecular medicine 6 39103698
2022 MEK1-dependent MondoA phosphorylation regulates glucose uptake in response to ketone bodies in colorectal cancer cells. Cancer science 4 36398713
2020 MondoA Is Required for Normal Myogenesis and Regulation of the Skeletal Muscle Glycogen Content in Mice. Diabetes & metabolism journal 4 32431117
2025 MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic ductal adenocarcinoma. bioRxiv : the preprint server for biology 1 40964310
2024 Genetic polymorphisms of LMX1B and MLXIP are associated with hip osteoarthritis in the Chinese population. Biomarkers in medicine 1 39263770
2026 MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America 0 41779777

Missed literature

Know a paper Affinage missed for MLXIP? Flag it for the maintainers and the community.

No submissions yet.