{"gene":"MLXIP","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2000,"finding":"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.","method":"Co-IP (in vivo association), leptomycin B treatment, reporter assays with heterologous NLS, deletion/domain mapping","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, functional domain mapping, pharmacological nuclear export inhibition, multiple orthogonal methods in foundational paper","pmids":["11073985"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Domain deletion/mutagenesis, co-IP, subcellular localization assays, CRM1 inhibitor (leptomycin B), 14-3-3 binding assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal domain-mapping experiments, pharmacological CRM1 inhibition, binding assays for 14-3-3, all in one rigorous study","pmids":["12446771"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Subcellular fractionation, salt/protease sensitivity assays, ChIP, reporter assays, knockdown/overexpression functional glycolysis assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — fractionation with biochemical controls, ChIP for direct promoter binding, loss- and gain-of-function glycolysis assays, multiple orthogonal methods","pmids":["16782875"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Reporter assays, HDAC inhibitor treatment, alpha-ketoglutarate supplementation, MondoA knockdown with glucose uptake measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (pharmacological, metabolite supplementation, genetic knockdown) in one study, single lab","pmids":["19706488"],"is_preprint":false},{"year":2010,"finding":"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.","method":"ChIP, reporter assays, glucose dose-response experiments, chromatin fractionation, HAT recruitment assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP and chromatin recruitment assays combined with reporter assays, multiple mechanistic steps dissected, single lab","pmids":["20385767"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Global transcriptome comparison, MondoA:Mlx functional assays, glucose uptake measurements under lactic acidosis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — transcriptome plus functional assays but mechanistic pathway placement relies on indirect evidence, single lab","pmids":["20844768"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Nuclear accumulation assays, TXNIP reporter/expression assays with metabolic inhibitors, MondoA-null and TXNIP-null MEF glucose uptake measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic null cell lines combined with pharmacological and metabolite approaches, multiple hexose substrates tested","pmids":["21908621"],"is_preprint":false},{"year":2012,"finding":"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.","method":"ChIP, MondoA/ChREBP knockdown, forced elevation/depletion of fructose 2,6-bisphosphate, nuclear translocation assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with genetic knockdown and metabolite manipulation, single lab","pmids":["23207906"],"is_preprint":false},{"year":2013,"finding":"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.","method":"TXNIP expression assays, pharmacological inhibitors of purine metabolism, genetic knockdowns of purine metabolic enzymes, AMPK/calcium pathway inhibition","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdowns combined with pharmacological approaches, single lab, AMPK independence confirmed","pmids":["23631812"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-IP (mTOR-MondoA interaction), mTOR inhibitor treatment, ROS treatment, TXNIP reporter/expression assays, MondoA-Mlx complex formation assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with functional consequences, pharmacological and genetic validation, single lab","pmids":["25332233"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Gene-targeted MondoA-/- mice, gene expression analysis, promoter analysis, exercise testing, metabolite measurement (lactate, alanine, fatty acids)","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout mouse with multiple metabolic readouts and promoter analysis, single lab","pmids":["25145386"],"is_preprint":false},{"year":2015,"finding":"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.","method":"MondoA/Mlx knockdown in Myc-overexpressing cells, metabolic profiling (NMR metabolomics), apoptosis assays, co-regulated gene identification and knockdown","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockdown with metabolomics and functional apoptosis readouts, multiple orthogonal approaches, replicated across cancer types","pmids":["25640402"],"is_preprint":false},{"year":2016,"finding":"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.","method":"High-throughput chemical screen, MondoA knockdown, TXNIP/ARRDC4 expression measurement, glucose uptake assays, in vivo mouse metabolic testing","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — chemical probe plus genetic knockdown with orthogonal in vitro and in vivo metabolic readouts","pmids":["27500491"],"is_preprint":false},{"year":2017,"finding":"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.","method":"MondoA knockdown, nuclear translocation assays, cAMP agonist treatment, TXNIP/ARRDC4 expression in human islets and cell lines","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with pharmacological manipulation and localization assays in primary human islets and cell lines, single lab","pmids":["29282201"],"is_preprint":false},{"year":2019,"finding":"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.","method":"mtATP measurement, hexokinase inhibition, G6P measurement, MondoA localization and ChIP assays, acidosis treatment","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection with metabolite measurements, pharmacological inhibition of hexokinase/VDAC, ChIP for promoter binding, multiple orthogonal methods","pmids":["30717828"],"is_preprint":false},{"year":2020,"finding":"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.","method":"MondoA knockdown, EMSA (electrophoretic mobility shift assay), site-directed mutagenesis of G6P-binding residues, molecular docking/in silico modeling","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus mutagenesis; in silico docking supports but does not independently confirm binding site","pmids":["31993438"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Muscle-specific MondoA knockout mice, C2C12 siRNA knockdown, myoblast functional assays (proliferation, migration, differentiation), glycogen measurement, TXNIP/GLUT4 expression analysis","journal":"Diabetes & metabolism journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific knockout with multiple functional readouts and molecular pathway analysis, single lab","pmids":["32431117"],"is_preprint":false},{"year":2020,"finding":"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.","method":"RNA-seq, metabolomics, MondoA knockdown, VDAC/HK interaction inhibition, mtATP and G6P measurement, cytotoxicity assays in cell lines and PDxO models","journal":"Cancer & metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown plus metabolomics and multiple pharmacological approaches, single lab","pmids":["33292639"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP/proteomics with site-directed mutagenesis and functional assays, single lab","pmids":["36398713"],"is_preprint":false},{"year":2022,"finding":"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.","method":"CRISPR/Cas9 and RNAi knockdown, metabolic pathway analysis (TCA cycle, OXPHOS), in vivo mouse model, patient dataset correlation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR and RNAi combined with metabolic measurements and in vivo model, single lab","pmids":["33908607"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-IP/pulldown (PRMT1-MLXIP interaction), ChIP (MLXIP recruitment to β-catenin promoter), PRMT1 knockdown/inhibition functional assays","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP plus ChIP in a single lab study, mechanistic follow-up limited to reporter/expression","pmids":["37554218"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic knockouts with multiple functional and metabolic readouts, SENP1 mechanism identified, replicated across multiple cancer models","pmids":["40846790"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Proximal tubule-specific MondoA knockout mice, Rubicon ablation epistasis, autophagy assays, TFEB/PGC-1α expression analysis, pharmacological TFEB upregulation","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific knockouts with genetic epistasis (Rubicon ablation rescue), multiple functional readouts, single lab","pmids":["38819935"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR knockout with genomic profiling, m6A analysis, epistasis rescue (ATF4), small-molecule inhibition in organoids; multiple orthogonal methods","pmids":["41779777"],"is_preprint":false}],"current_model":"MondoA (MLXIP) is a bHLH-leucine zipper transcription factor that forms an obligate heterocomplex with Mlx and functions as a central nutrient sensor: it localizes to the outer mitochondrial membrane and cytoplasm via CRM1-dependent nuclear export and 14-3-3 binding to its N-terminal MCR domains, translocates to the nucleus in response to glucose-6-phosphate (generated from cytoplasmic glucose and mitochondrial ATP via hexokinase) and adenine nucleotides, and then activates transcription of metabolic target genes (most prominently TXNIP, ARRDC4, LDHA, HKII, and PFKFB3) by binding CACGTG E-boxes and recruiting histone acetyltransferases; glutamine/TCA anaplerosis, mTOR binding, and MEK1-mediated tyrosine-222 phosphorylation antagonize MondoA activity, while SENP1-dependent deSUMOylation mediates lactic-acid-induced activation; through TXNIP induction MondoA creates a negative-feedback loop restraining glucose uptake and aerobic glycolysis, and it is co-opted by oncogenic MYC to reprogram cancer metabolism and suppress the Integrated Stress Response."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2000,"claim":"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","pmids":["11073985"],"confidence":"High","gaps":["Did not identify the activating signal driving nuclear entry","No endogenous target genes defined"]},{"year":2002,"claim":"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","pmids":["12446771"],"confidence":"High","gaps":["The extracellular/metabolic signal overriding retention was not identified","14-3-3 recruitment regulation undefined"]},{"year":2006,"claim":"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","pmids":["16782875"],"confidence":"High","gaps":["Identity of the mitochondrial tethering partner unknown","Did not link mitochondrial signal to nuclear activation"]},{"year":2009,"claim":"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","pmids":["19706488"],"confidence":"High","gaps":["Identity of the HDAC-dependent corepressor not defined","Direct glucose-derived activating metabolite still unknown at this stage"]},{"year":2010,"claim":"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","pmids":["20385767"],"confidence":"High","gaps":["Identity of the specific H3 acetyltransferase not pinned down","Molecular sensor of glucose signal still unresolved"]},{"year":2010,"claim":"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","pmids":["20844768"],"confidence":"Medium","gaps":["Mechanistic pathway placement relied on indirect evidence","Molecular link between acidosis and complex activation not established"]},{"year":2011,"claim":"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","pmids":["21908621"],"confidence":"High","gaps":["Direct binding of the phosphorylated hexose to MondoA not yet shown","Binding site unmapped"]},{"year":2013,"claim":"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","pmids":["23631812"],"confidence":"Medium","gaps":["Whether adenine nucleotides bind MondoA directly not shown","Single-lab study"]},{"year":2014,"claim":"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","pmids":["25332233"],"confidence":"Medium","gaps":["Structural basis of mTOR-MondoA interaction undefined","Single-lab study"]},{"year":2014,"claim":"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","pmids":["25145386"],"confidence":"Medium","gaps":["Mechanism of PGC-1α/PDK4 repression not detailed","Single-lab study"]},{"year":2015,"claim":"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","pmids":["25640402"],"confidence":"High","gaps":["Direct co-occupancy mechanism with Myc not fully resolved at this stage","Therapeutic targetability not yet shown"]},{"year":2016,"claim":"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","pmids":["27500491"],"confidence":"High","gaps":["Direct molecular target/binding mode of SBI-477 on MondoA not defined","Tissue selectivity not established"]},{"year":2017,"claim":"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","pmids":["29282201"],"confidence":"Medium","gaps":["Mechanism by which cAMP blocks shuttling unclear","Single-lab study"]},{"year":2019,"claim":"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","pmids":["30717828"],"confidence":"High","gaps":["Direct G6P-MondoA binding not yet demonstrated here","How acidosis raises mtATP mechanistically incomplete"]},{"year":2020,"claim":"Confirmed G6P as the direct activating ligand and mapped GKL139-141 as the binding residues.","evidence":"Knockdown, EMSA, site-directed mutagenesis, and molecular docking","pmids":["31993438"],"confidence":"Medium","gaps":["In silico docking does not independently confirm binding geometry","No high-resolution structure of the G6P-bound complex"]},{"year":2020,"claim":"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","pmids":["32431117"],"confidence":"Medium","gaps":["Direct versus indirect regulation of PTEN/PI3K/Akt unclear","Single-lab study"]},{"year":2020,"claim":"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","pmids":["33292639"],"confidence":"Medium","gaps":["How translation inhibition raises mtATP not fully resolved","Single-lab study"]},{"year":2022,"claim":"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","pmids":["36398713"],"confidence":"Medium","gaps":["Whether MEK1 phosphorylates Y222 directly versus via intermediary kinase not fully resolved","Single-lab study"]},{"year":2022,"claim":"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","pmids":["33908607"],"confidence":"Medium","gaps":["Transcriptional targets mediating PDH restriction not fully mapped","Single-lab study"]},{"year":2023,"claim":"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","pmids":["37554218"],"confidence":"Medium","gaps":["Whether this is Mlx-dependent or E-box-mediated unclear","Single co-IP plus ChIP without reciprocal mechanistic depth"]},{"year":2024,"claim":"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","pmids":["40846790"],"confidence":"High","gaps":["How SENP1 deSUMOylation activates MondoA mechanistically not fully detailed","SUMO acceptor site on MondoA not defined here"]},{"year":2024,"claim":"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","pmids":["38819935"],"confidence":"Medium","gaps":["Whether Rubicon and TFEB/PGC-1α are direct MondoA transcriptional targets unclear","Single-lab study"]},{"year":2025,"claim":"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","pmids":["41779777"],"confidence":"High","gaps":["How MondoA controls m6A and ATF4 translation mechanistically not resolved","Identity of small-molecule target site unclear"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,2,15]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[14,15,8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,14]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,3,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,19,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[21]}],"complexes":["MondoA:Mlx heterocomplex"],"partners":["MLX","MTOR","MAP2K1","PRMT1","SENP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HAP2","full_name":"MLX-interacting protein","aliases":["Class E basic helix-loop-helix protein 36","bHLHe36","Transcriptional activator MondoA"],"length_aa":919,"mass_kda":101.2,"function":"Binds DNA as a heterodimer with MLX and activates transcription. Binds to the canonical E box sequence 5'-CACGTG-3'. Plays a role in transcriptional activation of glycolytic target genes. Involved in glucose-responsive gene regulation","subcellular_location":"Cytoplasm; Nucleus; Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q9HAP2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MLXIP","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":77,"dependency_fraction":0.1038961038961039},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MLXIP","total_profiled":1310},"omim":[{"mim_id":"608090","title":"MLX-INTERACTING PROTEIN; MLXIP","url":"https://www.omim.org/entry/608090"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":123.0}],"url":"https://www.proteinatlas.org/search/MLXIP"},"hgnc":{"alias_symbol":["MONDOA","KIAA0867","MIR","bHLHe36"],"prev_symbol":[]},"alphafold":{"accession":"Q9HAP2","domains":[{"cath_id":"-","chopping":"123-145_156-184","consensus_level":"medium","plddt":69.6123,"start":123,"end":184},{"cath_id":"-","chopping":"813-917","consensus_level":"high","plddt":88.3598,"start":813,"end":917}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HAP2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HAP2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HAP2-F1-predicted_aligned_error_v6.png","plddt_mean":53.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MLXIP","jax_strain_url":"https://www.jax.org/strain/search?query=MLXIP"},"sequence":{"accession":"Q9HAP2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HAP2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HAP2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HAP2"}},"corpus_meta":[{"pmid":"25640402","id":"PMC_25640402","title":"Deregulated Myc requires MondoA/Mlx for metabolic reprogramming and tumorigenesis.","date":"2015","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/25640402","citation_count":176,"is_preprint":false},{"pmid":"19706488","id":"PMC_19706488","title":"Glutamine-dependent anapleurosis dictates glucose uptake and cell growth by regulating MondoA transcriptional activity.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19706488","citation_count":140,"is_preprint":false},{"pmid":"11073985","id":"PMC_11073985","title":"MondoA, a novel basic helix-loop-helix-leucine zipper transcriptional activator that constitutes a positive branch of a max-like network.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11073985","citation_count":112,"is_preprint":false},{"pmid":"20844768","id":"PMC_20844768","title":"Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA.","date":"2010","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20844768","citation_count":108,"is_preprint":false},{"pmid":"16782875","id":"PMC_16782875","title":"MondoA-Mlx heterodimers are candidate sensors of cellular energy status: mitochondrial localization and direct regulation of glycolysis.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16782875","citation_count":97,"is_preprint":false},{"pmid":"20385767","id":"PMC_20385767","title":"Glucose controls nuclear accumulation, promoter binding, and transcriptional activity of the MondoA-Mlx heterodimer.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20385767","citation_count":79,"is_preprint":false},{"pmid":"21908621","id":"PMC_21908621","title":"MondoA senses non-glucose sugars: regulation of thioredoxin-interacting protein (TXNIP) and the hexose transport 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transcriptional induction of thioredoxin-interacting protein.","date":"2013","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/23631812","citation_count":12,"is_preprint":false},{"pmid":"37240157","id":"PMC_37240157","title":"The Function of MondoA and ChREBP Nutrient-Sensing Factors in Metabolic Disease.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37240157","citation_count":11,"is_preprint":false},{"pmid":"31993438","id":"PMC_31993438","title":"Glucose-6-Phosphate Upregulates Txnip Expression by Interacting With MondoA.","date":"2020","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/31993438","citation_count":10,"is_preprint":false},{"pmid":"33292639","id":"PMC_33292639","title":"Protein synthesis inhibitors stimulate MondoA transcriptional activity by driving an accumulation of glucose 6-phosphate.","date":"2020","source":"Cancer & 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/40964310","citation_count":1,"is_preprint":false},{"pmid":"39263770","id":"PMC_39263770","title":"Genetic polymorphisms of LMX1B and MLXIP are associated with hip osteoarthritis in the Chinese population.","date":"2024","source":"Biomarkers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39263770","citation_count":1,"is_preprint":false},{"pmid":"41779777","id":"PMC_41779777","title":"MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic cancer.","date":"2026","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/41779777","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.06.680559","title":"Whole body MondoA deletion protects against diet-induced obesity through uncontrolled multi-organ substrate utilization and futile 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tissues","date":"2024-09-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.21.614255","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20072,"output_tokens":6699,"usd":0.080351,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15894,"output_tokens":6541,"usd":0.121497,"stage2_stop_reason":"end_turn"},"total_usd":0.201848,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP (in vivo association), leptomycin B treatment, reporter assays with heterologous NLS, deletion/domain mapping\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, functional domain mapping, pharmacological nuclear export inhibition, multiple orthogonal methods in foundational paper\",\n      \"pmids\": [\"11073985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Domain deletion/mutagenesis, co-IP, subcellular localization assays, CRM1 inhibitor (leptomycin B), 14-3-3 binding assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal domain-mapping experiments, pharmacological CRM1 inhibition, binding assays for 14-3-3, all in one rigorous study\",\n      \"pmids\": [\"12446771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Subcellular fractionation, salt/protease sensitivity assays, ChIP, reporter assays, knockdown/overexpression functional glycolysis assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — fractionation with biochemical controls, ChIP for direct promoter binding, loss- and gain-of-function glycolysis assays, multiple orthogonal methods\",\n      \"pmids\": [\"16782875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Reporter assays, HDAC inhibitor treatment, alpha-ketoglutarate supplementation, MondoA knockdown with glucose uptake measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (pharmacological, metabolite supplementation, genetic knockdown) in one study, single lab\",\n      \"pmids\": [\"19706488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP, reporter assays, glucose dose-response experiments, chromatin fractionation, HAT recruitment assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and chromatin recruitment assays combined with reporter assays, multiple mechanistic steps dissected, single lab\",\n      \"pmids\": [\"20385767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Global transcriptome comparison, MondoA:Mlx functional assays, glucose uptake measurements under lactic acidosis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — transcriptome plus functional assays but mechanistic pathway placement relies on indirect evidence, single lab\",\n      \"pmids\": [\"20844768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Nuclear accumulation assays, TXNIP reporter/expression assays with metabolic inhibitors, MondoA-null and TXNIP-null MEF glucose uptake measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null cell lines combined with pharmacological and metabolite approaches, multiple hexose substrates tested\",\n      \"pmids\": [\"21908621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP, MondoA/ChREBP knockdown, forced elevation/depletion of fructose 2,6-bisphosphate, nuclear translocation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with genetic knockdown and metabolite manipulation, single lab\",\n      \"pmids\": [\"23207906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"TXNIP expression assays, pharmacological inhibitors of purine metabolism, genetic knockdowns of purine metabolic enzymes, AMPK/calcium pathway inhibition\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdowns combined with pharmacological approaches, single lab, AMPK independence confirmed\",\n      \"pmids\": [\"23631812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP (mTOR-MondoA interaction), mTOR inhibitor treatment, ROS treatment, TXNIP reporter/expression assays, MondoA-Mlx complex formation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with functional consequences, pharmacological and genetic validation, single lab\",\n      \"pmids\": [\"25332233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Gene-targeted MondoA-/- mice, gene expression analysis, promoter analysis, exercise testing, metabolite measurement (lactate, alanine, fatty acids)\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout mouse with multiple metabolic readouts and promoter analysis, single lab\",\n      \"pmids\": [\"25145386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"MondoA/Mlx knockdown in Myc-overexpressing cells, metabolic profiling (NMR metabolomics), apoptosis assays, co-regulated gene identification and knockdown\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockdown with metabolomics and functional apoptosis readouts, multiple orthogonal approaches, replicated across cancer types\",\n      \"pmids\": [\"25640402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"High-throughput chemical screen, MondoA knockdown, TXNIP/ARRDC4 expression measurement, glucose uptake assays, in vivo mouse metabolic testing\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — chemical probe plus genetic knockdown with orthogonal in vitro and in vivo metabolic readouts\",\n      \"pmids\": [\"27500491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"MondoA knockdown, nuclear translocation assays, cAMP agonist treatment, TXNIP/ARRDC4 expression in human islets and cell lines\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with pharmacological manipulation and localization assays in primary human islets and cell lines, single lab\",\n      \"pmids\": [\"29282201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"mtATP measurement, hexokinase inhibition, G6P measurement, MondoA localization and ChIP assays, acidosis treatment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection with metabolite measurements, pharmacological inhibition of hexokinase/VDAC, ChIP for promoter binding, multiple orthogonal methods\",\n      \"pmids\": [\"30717828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"MondoA knockdown, EMSA (electrophoretic mobility shift assay), site-directed mutagenesis of G6P-binding residues, molecular docking/in silico modeling\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus mutagenesis; in silico docking supports but does not independently confirm binding site\",\n      \"pmids\": [\"31993438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Muscle-specific MondoA knockout mice, C2C12 siRNA knockdown, myoblast functional assays (proliferation, migration, differentiation), glycogen measurement, TXNIP/GLUT4 expression analysis\",\n      \"journal\": \"Diabetes & metabolism journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific knockout with multiple functional readouts and molecular pathway analysis, single lab\",\n      \"pmids\": [\"32431117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-seq, metabolomics, MondoA knockdown, VDAC/HK interaction inhibition, mtATP and G6P measurement, cytotoxicity assays in cell lines and PDxO models\",\n      \"journal\": \"Cancer & metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown plus metabolomics and multiple pharmacological approaches, single lab\",\n      \"pmids\": [\"33292639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP/proteomics with site-directed mutagenesis and functional assays, single lab\",\n      \"pmids\": [\"36398713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR/Cas9 and RNAi knockdown, metabolic pathway analysis (TCA cycle, OXPHOS), in vivo mouse model, patient dataset correlation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR and RNAi combined with metabolic measurements and in vivo model, single lab\",\n      \"pmids\": [\"33908607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP/pulldown (PRMT1-MLXIP interaction), ChIP (MLXIP recruitment to β-catenin promoter), PRMT1 knockdown/inhibition functional assays\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP plus ChIP in a single lab study, mechanistic follow-up limited to reporter/expression\",\n      \"pmids\": [\"37554218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic knockouts with multiple functional and metabolic readouts, SENP1 mechanism identified, replicated across multiple cancer models\",\n      \"pmids\": [\"40846790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Proximal tubule-specific MondoA knockout mice, Rubicon ablation epistasis, autophagy assays, TFEB/PGC-1α expression analysis, pharmacological TFEB upregulation\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific knockouts with genetic epistasis (Rubicon ablation rescue), multiple functional readouts, single lab\",\n      \"pmids\": [\"38819935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR knockout with genomic profiling, m6A analysis, epistasis rescue (ATF4), small-molecule inhibition in organoids; multiple orthogonal methods\",\n      \"pmids\": [\"41779777\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MondoA (MLXIP) is a bHLH-leucine zipper transcription factor that forms an obligate heterocomplex with Mlx and functions as a central nutrient sensor: it localizes to the outer mitochondrial membrane and cytoplasm via CRM1-dependent nuclear export and 14-3-3 binding to its N-terminal MCR domains, translocates to the nucleus in response to glucose-6-phosphate (generated from cytoplasmic glucose and mitochondrial ATP via hexokinase) and adenine nucleotides, and then activates transcription of metabolic target genes (most prominently TXNIP, ARRDC4, LDHA, HKII, and PFKFB3) by binding CACGTG E-boxes and recruiting histone acetyltransferases; glutamine/TCA anaplerosis, mTOR binding, and MEK1-mediated tyrosine-222 phosphorylation antagonize MondoA activity, while SENP1-dependent deSUMOylation mediates lactic-acid-induced activation; through TXNIP induction MondoA creates a negative-feedback loop restraining glucose uptake and aerobic glycolysis, and it is co-opted by oncogenic MYC to reprogram cancer metabolism and suppress the Integrated Stress Response.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #2]. 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 [#0, #1]. 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 [#1, #2]. 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 [#4]. 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 [#14, #15, #3, #8]. 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 [#2, #5, #9, #18, #21]. 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 [#11, #23]. In vivo, MondoA controls fuel selection, skeletal muscle glycogen and myogenesis, β-cell and T-cell glucose handling, and renal autophagy [#10, #16, #13, #21, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, leptomycin B nuclear export inhibition, and domain mapping with heterologous NLS reporters\",\n      \"pmids\": [\"11073985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the activating signal driving nuclear entry\", \"No endogenous target genes defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Domain deletion/mutagenesis, co-IP, CRM1 inhibition, and 14-3-3 binding assays\",\n      \"pmids\": [\"12446771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The extracellular/metabolic signal overriding retention was not identified\", \"14-3-3 recruitment regulation undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"Subcellular fractionation with salt/protease controls, ChIP, and loss/gain-of-function glycolysis assays in muscle and erythroblast cells\",\n      \"pmids\": [\"16782875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the mitochondrial tethering partner unknown\", \"Did not link mitochondrial signal to nuclear activation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed MondoA upstream of TXNIP in a glucose-uptake feedback loop and showed glutamine anaplerosis antagonizes it via HDAC corepressor recruitment.\",\n      \"evidence\": \"Reporter assays, HDAC inhibition, alpha-ketoglutarate supplementation, and knockdown with glucose uptake measurement\",\n      \"pmids\": [\"19706488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the HDAC-dependent corepressor not defined\", \"Direct glucose-derived activating metabolite still unknown at this stage\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Dissected glucose control into three sequential steps and showed nuclear localization alone is insufficient without continued signaling for HAT recruitment.\",\n      \"evidence\": \"ChIP, chromatin fractionation, glucose dose-response, and HAT recruitment assays\",\n      \"pmids\": [\"20385767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the specific H3 acetyltransferase not pinned down\", \"Molecular sensor of glucose signal still unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed the complex paradoxically responds to lactic acidosis like glucose to induce TXNIP/ARRDC4 and curb tumor glycolysis.\",\n      \"evidence\": \"Transcriptome comparison and MondoA:Mlx functional assays under lactic acidosis\",\n      \"pmids\": [\"20844768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic pathway placement relied on indirect evidence\", \"Molecular link between acidosis and complex activation not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Broadened the sensing repertoire to non-glucose hexoses and their 6-phosphates, narrowing the activating signal toward hexose-phosphate metabolites.\",\n      \"evidence\": \"Nuclear accumulation and TXNIP assays with metabolic inhibitors in MondoA-null and TXNIP-null MEFs\",\n      \"pmids\": [\"21908621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding of the phosphorylated hexose to MondoA not yet shown\", \"Binding site unmapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated MondoA additionally senses adenine nucleotides independently of AMPK and calcium, indicating multi-metabolite integration.\",\n      \"evidence\": \"TXNIP expression with purine-metabolism inhibitors, enzyme knockdowns, and AMPK/calcium pathway inhibition\",\n      \"pmids\": [\"23631812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether adenine nucleotides bind MondoA directly not shown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified mTOR as a cytoplasmic MondoA-binding antagonist that blocks complex formation, and established a reciprocal MondoA-TXNIP suppression of mTORC1.\",\n      \"evidence\": \"Reciprocal co-IP, mTOR inhibitor and ROS treatment, complex-formation and TXNIP assays\",\n      \"pmids\": [\"25332233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of mTOR-MondoA interaction undefined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed an in vivo role in fuel selection: MondoA represses PGC-1α-driven PDK4 transcription, directing pyruvate fate.\",\n      \"evidence\": \"MondoA-/- mice with exercise testing, promoter analysis, and metabolite measurement\",\n      \"pmids\": [\"25145386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PGC-1α/PDK4 repression not detailed\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that oncogenic Myc depends on MondoA:Mlx for metabolic reprogramming and tumor survival, defining a co-regulated metabolic gene set.\",\n      \"evidence\": \"MondoA/Mlx knockdown in Myc-overexpressing cells with NMR metabolomics and apoptosis assays\",\n      \"pmids\": [\"25640402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct co-occupancy mechanism with Myc not fully resolved at this stage\", \"Therapeutic targetability not yet shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided a druggable handle: the small molecule SBI-477 deactivates MondoA, lowers TXNIP/ARRDC4, enhances glucose uptake, and improves glucose tolerance in vivo.\",\n      \"evidence\": \"Chemical screen, MondoA knockdown, expression and glucose uptake assays, and high-fat-diet mouse testing\",\n      \"pmids\": [\"27500491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target/binding mode of SBI-477 on MondoA not defined\", \"Tissue selectivity not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed MondoA, not ChREBP, is the dominant glucose-responsive factor in human β-cells, with cAMP signaling suppressing its nuclear shuttling.\",\n      \"evidence\": \"Knockdown, nuclear translocation and TXNIP/ARRDC4 assays with cAMP agonists in human islets and EndoC-βH1\",\n      \"pmids\": [\"29282201\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which cAMP blocks shuttling unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Unified mitochondrial localization with metabolite sensing: acidosis raises mtATP, which mitochondria-bound hexokinase uses to generate G6P that activates MondoA at TXNIP/ARRDC4 promoters.\",\n      \"evidence\": \"mtATP and G6P measurement, hexokinase/VDAC inhibition, localization and ChIP assays under acidosis\",\n      \"pmids\": [\"30717828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct G6P-MondoA binding not yet demonstrated here\", \"How acidosis raises mtATP mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed G6P as the direct activating ligand and mapped GKL139-141 as the binding residues.\",\n      \"evidence\": \"Knockdown, EMSA, site-directed mutagenesis, and molecular docking\",\n      \"pmids\": [\"31993438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In silico docking does not independently confirm binding geometry\", \"No high-resolution structure of the G6P-bound complex\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended in vivo function to myogenesis and muscle glycogen control, linking MondoA loss to PTEN/PI3K/Akt signaling and TXNIP-GLUT4-driven glucose uptake.\",\n      \"evidence\": \"Muscle-specific knockout mice, C2C12 knockdown, functional myoblast assays, and glycogen/GLUT4 measurement\",\n      \"pmids\": [\"32431117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect regulation of PTEN/PI3K/Akt unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"RNA-seq, metabolomics, knockdown, VDAC/HK inhibition, and cytotoxicity assays in cell lines and PDxO\",\n      \"pmids\": [\"33292639\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How translation inhibition raises mtATP not fully resolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP/MS, MEK1 knockdown, Y222 mutagenesis, translocation and TXNIP reporter assays\",\n      \"pmids\": [\"36398713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MEK1 phosphorylates Y222 directly versus via intermediary kinase not fully resolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed MondoA restricts oxidative phosphorylation by limiting pyruvate dehydrogenase activity, supporting B-ALL transformation.\",\n      \"evidence\": \"CRISPR and RNAi knockdown, TCA/OXPHOS metabolic analysis, and in vivo model with patient dataset correlation\",\n      \"pmids\": [\"33908607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional targets mediating PDH restriction not fully mapped\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-canonical role: PRMT1 recruits MLXIP to the β-catenin promoter to activate β-catenin signaling in gastric cancer.\",\n      \"evidence\": \"Co-IP/pulldown and ChIP with PRMT1 knockdown/inhibition functional assays\",\n      \"pmids\": [\"37554218\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this is Mlx-dependent or E-box-mediated unclear\", \"Single co-IP plus ChIP without reciprocal mechanistic depth\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cell-type-specific knockouts, TXNIP and SENP1 assays, glucose/glycolysis measurement, cytotoxicity and anti-PD-1 tumor models\",\n      \"pmids\": [\"40846790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SENP1 deSUMOylation activates MondoA mechanistically not fully detailed\", \"SUMO acceptor site on MondoA not defined here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed renal MondoA suppresses Rubicon to permit autophagy and drives TFEB-PGC-1α-dependent mitochondrial biogenesis, protecting against acute kidney injury.\",\n      \"evidence\": \"Proximal-tubule-specific knockout with Rubicon ablation epistasis, autophagy and TFEB/PGC-1α assays\",\n      \"pmids\": [\"38819935\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Rubicon and TFEB/PGC-1α are direct MondoA transcriptional targets unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a mechanistic link between MondoA, deregulated MYC, and the Integrated Stress Response, with MondoA sustaining ATF4 translation in MYC-amplified PDAC.\",\n      \"evidence\": \"CRISPR knockout, ChIP-seq, m6A profiling, ATF4 rescue, and small-molecule inhibition in PDAC cells and organoids\",\n      \"pmids\": [\"41779777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MondoA controls m6A and ATF4 translation mechanistically not resolved\", \"Identity of small-molecule target site unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 2, 15]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [14, 15, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [2, 14]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 3, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 19, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"complexes\": [\"MondoA:Mlx heterocomplex\"],\n    \"partners\": [\"MLX\", \"MTOR\", \"MAP2K1\", \"PRMT1\", \"SENP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}