{"gene":"ARMCX3","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2012,"finding":"ARMCX3 (Alex3) localizes to mitochondria and regulates mitochondrial dynamics and trafficking in neurons. Alex3 physically interacts with the Kinesin/Miro/Trak2 complex in a Ca2+-dependent manner, placing it in the motor adaptor complex that controls mitochondrial movement.","method":"Subcellular fractionation/localization, co-immunoprecipitation of Alex3 with Miro and Trak2, overexpression/knockdown with mitochondrial trafficking readout in neurons","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying complex components, live-imaging of mitochondrial trafficking, Ca2+-dependence demonstrated, replicated context in later papers","pmids":["22569362"],"is_preprint":false},{"year":2009,"finding":"ARMCX3 is an integral membrane protein of the mitochondrial outer membrane that physically interacts with the transcription factor Sox10. In the cytoplasm, Sox10 is peripherally associated with the mitochondrial outer membrane, and overexpression of ARMCX3 increases the amount of mitochondrially associated Sox10. ARMCX3 lacks intrinsic transcriptional activity but enhances Sox10-mediated transactivation of the nicotinic acetylcholine receptor alpha3 and beta4 subunit gene promoters.","method":"Co-immunoprecipitation (Sox10–ARMCX3 interaction), membrane fractionation (integral membrane protein characterization), luciferase reporter assays (transactivation), overexpression studies in neuronal-like cell lines","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, biochemical fractionation, and functional reporter assay in a single lab with multiple orthogonal methods","pmids":["19304657"],"is_preprint":false},{"year":2013,"finding":"The non-canonical Wnt/PKC pathway regulates mitochondrial dynamics by inducing degradation of Alex3 (ARMCX3). Wnt treatment attenuates Alex3-induced mitochondrial aggregation by reducing Alex3 protein levels; the canonical Wnt pathway does not affect this, but the Wnt/PKC non-canonical pathway controls both mitochondrial aggregation and Alex3 protein stability.","method":"Overexpression of Alex3 in HEK293 cells with Wnt treatment, protein level analysis (immunoblot), pharmacological inhibition of PKC pathway, mitochondrial morphology readout","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway-specific pharmacological dissection, protein degradation assay, and mitochondrial phenotype readout; single lab, two orthogonal methods","pmids":["23844091"],"is_preprint":false},{"year":2016,"finding":"In chick spinal cord, ARMCX3 overexpression regulates neural progenitor proliferation and neural maturation, and these phenotypic effects require its mitochondrial localization. ARMCX3 acts as an inhibitor of Wnt-β-catenin signaling in neural development.","method":"In ovo electroporation of shRNA (knockdown) and overexpression constructs in chick neural tube, mitochondrial localization mutants, BrdU/EdU proliferation assays, neuronal differentiation markers","journal":"Frontiers in Cellular Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with localization mutants in vivo model, single lab","pmids":["26973462"],"is_preprint":false},{"year":2017,"finding":"ARMCX3 (Alex3) overexpression in non-small cell lung cancer cells suppresses invasion and migration by downregulating phospho-AKT and Slug and upregulating E-cadherin, placing ARMCX3 upstream of the AKT/Slug/E-cadherin axis.","method":"Overexpression in lung cancer cell lines, invasion/migration assays (Transwell), immunoblot for p-AKT, Slug, E-cadherin","journal":"Tumour Biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression approach with pathway readout but no rescue or mutagenesis","pmids":["28705116"],"is_preprint":false},{"year":2021,"finding":"ARMCX3 mediates hepatic tumorigenesis under dietary lipotoxicity. ARMCX3 knockout in mice protected against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis, promoting apoptosis and macrophage infiltration. SOX9 was identified as a mediator of ARMCX3 effects in hepatic cells, with the SOX9–ARMCX3 interaction required for ARMCX3-driven hepatic cell proliferation.","method":"Inducible ARMCX3 knockout mouse model, high-fat diet + diethylnitrosamine carcinogenesis model, HCC cell line knockdown/overexpression, co-immunoprecipitation (ARMCX3–SOX9 interaction), viability/clonality/migration assays","journal":"Cancers","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO model with defined phenotype, Co-IP for SOX9 interaction, and cell-line gain/loss-of-function; multiple orthogonal methods","pmids":["33807672"],"is_preprint":false},{"year":2022,"finding":"ARMCX3 is a negative regulator of white adipose tissue browning. Armcx3-KO mice show induced WAT browning, and adenoviral overexpression of ARMCX3 in differentiating brown adipocytes downregulates thermogenesis-related genes and reduces mitochondrial oxidative activity. Armcx3 expression is repressed by cold or β3-adrenergic thermogenic stimulation and upregulated by obesity.","method":"Armcx3 knockout mice (adipose tissue characterization), adenoviral overexpression in brown adipocyte cultures, siRNA knockdown, gene expression (qPCR), mitochondrial respiration assay, histology","journal":"International Journal of Obesity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with phenotype, cell culture gain/loss-of-function with functional mitochondrial readout; single lab, multiple methods","pmids":["35705702"],"is_preprint":false},{"year":2024,"finding":"ARMCX3 (Alex3) forms a mammalian-specific mitochondrial complex with Gαq and the Miro1/Trak2 adaptor complex. Gαq activation inhibits mitochondrial trafficking in neurons independently of the canonical PLCβ pathway. CNS-specific Alex3 knockout mice showed that Alex3 is required for Gαq-mediated effects on mitochondrial trafficking and dendritic growth. Alex3-deficient mice had elevated ER stress response proteins, increased neuronal death, motor neuron loss, and severe motor deficits.","method":"Mitoproteome/mass spectrometry (Gαq–Alex3 interaction), co-immunoprecipitation, CNS-specific conditional Alex3 knockout mouse, live-imaging of mitochondrial trafficking, dendritic complexity analysis, histological assessment of neuronal death and motor neuron loss","journal":"Science Signaling","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mitoproteome MS identification of complex, Co-IP validation, in vivo conditional KO with multiple defined phenotypes, trafficking assays; multiple orthogonal methods in single rigorous study","pmids":["38320000"],"is_preprint":false},{"year":2024,"finding":"A regulatory axis involving Prx II, the transcription factor ATF3, and miR-181b-5p collectively modulates Armcx3 expression, which is implicated in mitochondrial transport. Prx II deficiency reduces Armcx3 levels via this pathway in neuronal (HT22) cells.","method":"RNA sequencing, Prx II knockdown/overexpression in HT22 cells, bioinformatic pathway analysis, miR-181b-5p target validation","journal":"Cell Communication and Signaling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily transcriptomic/bioinformatic with limited direct mechanistic validation of the axis for ARMCX3 specifically","pmids":["38637880"],"is_preprint":false},{"year":2024,"finding":"ARMCX3 knockdown in dental pulp stem cells (hDPSCs) accelerates neural differentiation and reduces inflammatory cytokine levels under LPS-induced inflammation. ARMCX3 overexpression increases ROS production, and ROS inhibition reverses the effects of ARMCX3 overexpression, indicating ARMCX3 regulates neural differentiation and inflammation at least partly through ROS signaling.","method":"Lentiviral knockdown and overexpression in hDPSCs, ROS measurement (specific kits), immunofluorescence, qRT-PCR, ELISA, ROS inhibitor rescue experiment","journal":"Heliyon","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, gain/loss-of-function with pharmacological rescue; mechanism upstream of ROS not defined","pmids":["39296219"],"is_preprint":false}],"current_model":"ARMCX3 (Alex3) is a Eutherian-specific integral membrane protein of the mitochondrial outer membrane that forms a Ca2+-sensitive complex with Miro1/Trak2 and Kinesin motors to control mitochondrial trafficking and dynamics in neurons; it further interacts with Gαq to transduce GPCR signals to the mitochondrial transport machinery independently of PLCβ, is subject to degradation via the non-canonical Wnt/PKC pathway, interacts with Sox10 to potentiate transcriptional activity, and interacts with SOX9 to promote hepatic cell proliferation, with loss of ARMCX3 causing neuronal death, motor deficits, and protection from hepatocarcinogenesis."},"narrative":{"mechanistic_narrative":"ARMCX3 (Alex3) is an integral membrane protein of the mitochondrial outer membrane that controls mitochondrial dynamics and trafficking, particularly in neurons [PMID:22569362, PMID:19304657]. It assembles into the Kinesin/Miro1/Trak2 motor adaptor complex in a Ca2+-dependent manner, positioning it as a regulator of mitochondrial movement [PMID:22569362], and it further recruits Gαq into this complex to transduce GPCR signals onto the transport machinery independently of the canonical PLCβ pathway; CNS-specific loss of ARMCX3 abolishes Gαq-mediated control of mitochondrial trafficking and dendritic growth and causes ER stress, neuronal and motor neuron death, and severe motor deficits [PMID:38320000]. ARMCX3 protein stability is regulated by the non-canonical Wnt/PKC pathway, which drives its degradation and thereby modulates mitochondrial morphology [PMID:23844091]. Beyond its trafficking role, ARMCX3 interacts with the transcription factors Sox10 and SOX9: it binds Sox10 at the outer mitochondrial membrane and potentiates Sox10-dependent transactivation without intrinsic transcriptional activity [PMID:19304657], and its interaction with SOX9 drives hepatic cell proliferation, with ARMCX3 knockout protecting mice against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis [PMID:33807672]. ARMCX3 also acts as a negative regulator of white adipose tissue browning and mitochondrial oxidative activity, with its expression repressed by thermogenic stimulation and induced by obesity [PMID:35705702].","teleology":[{"year":2009,"claim":"Established the first molecular partner of ARMCX3 by showing it is an outer mitochondrial membrane protein that binds the transcription factor Sox10 and potentiates Sox10-driven transcription, linking a mitochondrial protein to gene regulation.","evidence":"Co-IP, membrane fractionation, and luciferase reporter assays in neuronal-like cell lines","pmids":["19304657"],"confidence":"Medium","gaps":["Mechanism by which a membrane-anchored protein influences nuclear transactivation not defined","Single-lab interaction without reciprocal in vivo validation"]},{"year":2012,"claim":"Defined ARMCX3's core cellular function by placing it within the Kinesin/Miro/Trak2 motor adaptor complex and showing Ca2+-dependent regulation of mitochondrial trafficking in neurons.","evidence":"Subcellular fractionation, reciprocal Co-IP with Miro and Trak2, live-imaging of mitochondrial trafficking with overexpression/knockdown","pmids":["22569362"],"confidence":"High","gaps":["Structural basis of Ca2+ sensing within the complex unresolved","Did not address upstream signals controlling complex assembly"]},{"year":2013,"claim":"Identified an upstream regulatory input controlling ARMCX3 by showing the non-canonical Wnt/PKC pathway degrades the protein and thereby modulates mitochondrial morphology.","evidence":"Wnt treatment and PKC pharmacological inhibition with immunoblot and mitochondrial morphology readout in HEK293 cells","pmids":["23844091"],"confidence":"Medium","gaps":["Specific E3 ligase/degradation machinery not identified","Performed in non-neuronal overexpression system"]},{"year":2016,"claim":"Connected ARMCX3's mitochondrial localization to developmental phenotypes, showing it regulates neural progenitor proliferation and inhibits Wnt-β-catenin signaling in a localization-dependent manner.","evidence":"In ovo electroporation of knockdown/overexpression and localization mutants in chick neural tube with proliferation and differentiation markers","pmids":["26973462"],"confidence":"Medium","gaps":["Molecular link between mitochondrial anchoring and Wnt inhibition not defined","Single in vivo model"]},{"year":2021,"claim":"Extended ARMCX3 function to disease pathophysiology by demonstrating it drives hepatic tumorigenesis under lipotoxicity through a SOX9 interaction, with knockout being protective.","evidence":"Inducible ARMCX3 KO mouse with high-fat-diet/diethylnitrosamine carcinogenesis, HCC cell line gain/loss-of-function, and Co-IP for SOX9","pmids":["33807672"],"confidence":"High","gaps":["How mitochondrial ARMCX3 engages the SOX9 transcriptional program mechanistically unclear","Relationship between the Sox10 and SOX9 interactions not addressed"]},{"year":2022,"claim":"Revealed a metabolic role for ARMCX3 as a negative regulator of adipose browning and mitochondrial oxidative activity responsive to thermogenic and obesogenic signals.","evidence":"Armcx3 KO mice, adenoviral overexpression and siRNA in brown adipocytes, qPCR, mitochondrial respiration assays, histology","pmids":["35705702"],"confidence":"Medium","gaps":["Direct molecular effectors of thermogenic gene repression not identified","Link to its motor-complex function in adipocytes unexplored"]},{"year":2024,"claim":"Integrated ARMCX3 into GPCR signaling by showing it recruits Gαq to the Miro1/Trak2 complex to arrest mitochondrial transport independently of PLCβ, with conditional knockout producing severe neurodegenerative phenotypes.","evidence":"Mitoproteome mass spectrometry, Co-IP, CNS-specific conditional KO mouse, live-imaging of trafficking, dendritic and histological analyses","pmids":["38320000"],"confidence":"High","gaps":["Biochemical mechanism by which Gαq engagement halts the motor not resolved","Receptors upstream of the Gαq input not defined"]},{"year":2024,"claim":"Proposed transcriptional/post-transcriptional control of Armcx3 expression via a Prx II–ATF3–miR-181b-5p axis affecting mitochondrial transport.","evidence":"RNA-seq, Prx II knockdown/overexpression in HT22 cells, bioinformatics, miR-181b-5p target validation","pmids":["38637880"],"confidence":"Low","gaps":["Primarily transcriptomic/bioinformatic with limited direct validation for ARMCX3","Causal contribution of each node to ARMCX3 function untested"]},{"year":2024,"claim":"Linked ARMCX3 to ROS signaling in regulating neural differentiation and inflammation in dental pulp stem cells.","evidence":"Lentiviral knockdown/overexpression in hDPSCs with ROS measurement and ROS-inhibitor rescue, qRT-PCR, ELISA","pmids":["39296219"],"confidence":"Low","gaps":["Mechanism upstream of ROS not defined","Single-lab gain/loss-of-function without genetic rescue"]},{"year":null,"claim":"How ARMCX3's dual roles — as a mitochondrial motor adaptor and as a partner of transcription factors (Sox10, SOX9) — are mechanistically coordinated, and what the structural basis of its Ca2+- and Gαq-dependent control of the Miro1/Trak2 complex is, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the ARMCX3/Miro1/Trak2/Gαq complex","Mechanism connecting mitochondrial anchoring to transcriptional partner regulation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,7]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,7]}],"complexes":["Miro1/Trak2/Kinesin motor adaptor complex"],"partners":["MIRO1","TRAK2","GNAQ","SOX10","SOX9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UH62","full_name":"Armadillo repeat-containing X-linked protein 3","aliases":["ARM protein lost in epithelial cancers on chromosome X 3","Protein ALEX3"],"length_aa":379,"mass_kda":42.5,"function":"Regulates mitochondrial aggregation and transport in axons in living neurons. May link mitochondria to the TRAK2-kinesin motor complex via its interaction with Miro and TRAK2. Mitochondrial distribution and dynamics is regulated through ARMCX3 protein degradation, which is promoted by PCK and negatively regulated by WNT1. Enhances the SOX10-mediated transactivation of the neuronal acetylcholine receptor subunit alpha-3 and beta-4 subunit gene promoters","subcellular_location":"Mitochondrion outer membrane; Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UH62/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARMCX3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"IPO5","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ARMCX3","total_profiled":1310},"omim":[{"mim_id":"300364","title":"ARMADILLO REPEAT-CONTAINING PROTEIN, X-LINKED 3; ARMCX3","url":"https://www.omim.org/entry/300364"},{"mim_id":"300363","title":"ARMADILLO REPEAT-CONTAINING PROTEIN, X-LINKED 2; ARMCX2","url":"https://www.omim.org/entry/300363"},{"mim_id":"300362","title":"ARMADILLO REPEAT-CONTAINING PROTEIN, X-LINKED 1; ARMCX1","url":"https://www.omim.org/entry/300362"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ARMCX3"},"hgnc":{"alias_symbol":["ALEX3","GASP6"],"prev_symbol":[]},"alphafold":{"accession":"Q9UH62","domains":[{"cath_id":"1.25.10.10","chopping":"115-199","consensus_level":"medium","plddt":94.5221,"start":115,"end":199},{"cath_id":"1.25.10","chopping":"235-379","consensus_level":"medium","plddt":85.4047,"start":235,"end":379}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UH62","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UH62-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UH62-F1-predicted_aligned_error_v6.png","plddt_mean":76.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARMCX3","jax_strain_url":"https://www.jax.org/strain/search?query=ARMCX3"},"sequence":{"accession":"Q9UH62","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UH62.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UH62/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UH62"}},"corpus_meta":[{"pmid":"22569362","id":"PMC_22569362","title":"The Eutherian Armcx genes regulate mitochondrial trafficking in neurons and interact with Miro and Trak2.","date":"2012","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/22569362","citation_count":89,"is_preprint":false},{"pmid":"11162520","id":"PMC_11162520","title":"ALEX1, a novel human armadillo repeat protein that is expressed differentially in normal tissues and carcinomas.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11162520","citation_count":58,"is_preprint":false},{"pmid":"35990678","id":"PMC_35990678","title":"Screening of crosstalk and pyroptosis-related genes linking periodontitis and osteoporosis based on bioinformatics and machine learning.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35990678","citation_count":42,"is_preprint":false},{"pmid":"19304657","id":"PMC_19304657","title":"The armadillo repeat-containing protein, ARMCX3, physically and functionally interacts with the developmental regulatory factor Sox10.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19304657","citation_count":32,"is_preprint":false},{"pmid":"34446064","id":"PMC_34446064","title":"Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program.","date":"2021","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34446064","citation_count":26,"is_preprint":false},{"pmid":"23844091","id":"PMC_23844091","title":"The non-canonical Wnt/PKC pathway regulates mitochondrial dynamics through degradation of the arm-like domain-containing protein Alex3.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23844091","citation_count":24,"is_preprint":false},{"pmid":"26973462","id":"PMC_26973462","title":"Function of Armcx3 and Armc10/SVH Genes in the Regulation of Progenitor Proliferation and Neural Differentiation in the Chicken Spinal Cord.","date":"2016","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26973462","citation_count":18,"is_preprint":false},{"pmid":"33267763","id":"PMC_33267763","title":"GPRASP/ARMCX Protein Family: Potential Involvement in Health and Diseases Revealed by their Novel Interacting Partners.","date":"2021","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33267763","citation_count":15,"is_preprint":false},{"pmid":"35426957","id":"PMC_35426957","title":"Diverse and mobile: eccDNA-based identification of carrot low-copy-number LTR retrotransposons active in callus cultures.","date":"2022","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/35426957","citation_count":14,"is_preprint":false},{"pmid":"28705116","id":"PMC_28705116","title":"Alex3 suppresses non-small cell lung cancer invasion via AKT/Slug/E-cadherin pathway.","date":"2017","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28705116","citation_count":11,"is_preprint":false},{"pmid":"33807672","id":"PMC_33807672","title":"ARMCX3 Mediates Susceptibility to Hepatic Tumorigenesis Promoted by Dietary Lipotoxicity.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33807672","citation_count":10,"is_preprint":false},{"pmid":"38320000","id":"PMC_38320000","title":"A mammalian-specific Alex3/Gαq protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival.","date":"2024","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/38320000","citation_count":5,"is_preprint":false},{"pmid":"39296219","id":"PMC_39296219","title":"ARMCX3 regulates ROS signaling, affects neural differentiation and inflammatory microenvironment in dental pulp stem cells.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39296219","citation_count":5,"is_preprint":false},{"pmid":"31566019","id":"PMC_31566019","title":"Epigenome- and Transcriptome-wide Changes in Muscle Stem Cells from Low Birth Weight Men.","date":"2019","source":"Endocrine research","url":"https://pubmed.ncbi.nlm.nih.gov/31566019","citation_count":5,"is_preprint":false},{"pmid":"38657876","id":"PMC_38657876","title":"Regulatory role of PDK1 via integrated gene analysis of mitochondria-immune response in periodontitis.","date":"2024","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/38657876","citation_count":5,"is_preprint":false},{"pmid":"40202610","id":"PMC_40202610","title":"ITGA1, the alpha 1 subunit of integrin receptor, is a novel marker of drug-resistant senescent melanoma cells in vitro.","date":"2025","source":"Archives of 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CCS","url":"https://pubmed.ncbi.nlm.nih.gov/38637880","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12117,"output_tokens":2826,"usd":0.039371,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10269,"output_tokens":3290,"usd":0.066797,"stage2_stop_reason":"end_turn"},"total_usd":0.106168,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"ARMCX3 (Alex3) localizes to mitochondria and regulates mitochondrial dynamics and trafficking in neurons. Alex3 physically interacts with the Kinesin/Miro/Trak2 complex in a Ca2+-dependent manner, placing it in the motor adaptor complex that controls mitochondrial movement.\",\n      \"method\": \"Subcellular fractionation/localization, co-immunoprecipitation of Alex3 with Miro and Trak2, overexpression/knockdown with mitochondrial trafficking readout in neurons\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying complex components, live-imaging of mitochondrial trafficking, Ca2+-dependence demonstrated, replicated context in later papers\",\n      \"pmids\": [\"22569362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ARMCX3 is an integral membrane protein of the mitochondrial outer membrane that physically interacts with the transcription factor Sox10. In the cytoplasm, Sox10 is peripherally associated with the mitochondrial outer membrane, and overexpression of ARMCX3 increases the amount of mitochondrially associated Sox10. ARMCX3 lacks intrinsic transcriptional activity but enhances Sox10-mediated transactivation of the nicotinic acetylcholine receptor alpha3 and beta4 subunit gene promoters.\",\n      \"method\": \"Co-immunoprecipitation (Sox10–ARMCX3 interaction), membrane fractionation (integral membrane protein characterization), luciferase reporter assays (transactivation), overexpression studies in neuronal-like cell lines\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, biochemical fractionation, and functional reporter assay in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19304657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The non-canonical Wnt/PKC pathway regulates mitochondrial dynamics by inducing degradation of Alex3 (ARMCX3). Wnt treatment attenuates Alex3-induced mitochondrial aggregation by reducing Alex3 protein levels; the canonical Wnt pathway does not affect this, but the Wnt/PKC non-canonical pathway controls both mitochondrial aggregation and Alex3 protein stability.\",\n      \"method\": \"Overexpression of Alex3 in HEK293 cells with Wnt treatment, protein level analysis (immunoblot), pharmacological inhibition of PKC pathway, mitochondrial morphology readout\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway-specific pharmacological dissection, protein degradation assay, and mitochondrial phenotype readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"23844091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In chick spinal cord, ARMCX3 overexpression regulates neural progenitor proliferation and neural maturation, and these phenotypic effects require its mitochondrial localization. ARMCX3 acts as an inhibitor of Wnt-β-catenin signaling in neural development.\",\n      \"method\": \"In ovo electroporation of shRNA (knockdown) and overexpression constructs in chick neural tube, mitochondrial localization mutants, BrdU/EdU proliferation assays, neuronal differentiation markers\",\n      \"journal\": \"Frontiers in Cellular Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with localization mutants in vivo model, single lab\",\n      \"pmids\": [\"26973462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ARMCX3 (Alex3) overexpression in non-small cell lung cancer cells suppresses invasion and migration by downregulating phospho-AKT and Slug and upregulating E-cadherin, placing ARMCX3 upstream of the AKT/Slug/E-cadherin axis.\",\n      \"method\": \"Overexpression in lung cancer cell lines, invasion/migration assays (Transwell), immunoblot for p-AKT, Slug, E-cadherin\",\n      \"journal\": \"Tumour Biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression approach with pathway readout but no rescue or mutagenesis\",\n      \"pmids\": [\"28705116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ARMCX3 mediates hepatic tumorigenesis under dietary lipotoxicity. ARMCX3 knockout in mice protected against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis, promoting apoptosis and macrophage infiltration. SOX9 was identified as a mediator of ARMCX3 effects in hepatic cells, with the SOX9–ARMCX3 interaction required for ARMCX3-driven hepatic cell proliferation.\",\n      \"method\": \"Inducible ARMCX3 knockout mouse model, high-fat diet + diethylnitrosamine carcinogenesis model, HCC cell line knockdown/overexpression, co-immunoprecipitation (ARMCX3–SOX9 interaction), viability/clonality/migration assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO model with defined phenotype, Co-IP for SOX9 interaction, and cell-line gain/loss-of-function; multiple orthogonal methods\",\n      \"pmids\": [\"33807672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ARMCX3 is a negative regulator of white adipose tissue browning. Armcx3-KO mice show induced WAT browning, and adenoviral overexpression of ARMCX3 in differentiating brown adipocytes downregulates thermogenesis-related genes and reduces mitochondrial oxidative activity. Armcx3 expression is repressed by cold or β3-adrenergic thermogenic stimulation and upregulated by obesity.\",\n      \"method\": \"Armcx3 knockout mice (adipose tissue characterization), adenoviral overexpression in brown adipocyte cultures, siRNA knockdown, gene expression (qPCR), mitochondrial respiration assay, histology\",\n      \"journal\": \"International Journal of Obesity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with phenotype, cell culture gain/loss-of-function with functional mitochondrial readout; single lab, multiple methods\",\n      \"pmids\": [\"35705702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ARMCX3 (Alex3) forms a mammalian-specific mitochondrial complex with Gαq and the Miro1/Trak2 adaptor complex. Gαq activation inhibits mitochondrial trafficking in neurons independently of the canonical PLCβ pathway. CNS-specific Alex3 knockout mice showed that Alex3 is required for Gαq-mediated effects on mitochondrial trafficking and dendritic growth. Alex3-deficient mice had elevated ER stress response proteins, increased neuronal death, motor neuron loss, and severe motor deficits.\",\n      \"method\": \"Mitoproteome/mass spectrometry (Gαq–Alex3 interaction), co-immunoprecipitation, CNS-specific conditional Alex3 knockout mouse, live-imaging of mitochondrial trafficking, dendritic complexity analysis, histological assessment of neuronal death and motor neuron loss\",\n      \"journal\": \"Science Signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mitoproteome MS identification of complex, Co-IP validation, in vivo conditional KO with multiple defined phenotypes, trafficking assays; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"38320000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A regulatory axis involving Prx II, the transcription factor ATF3, and miR-181b-5p collectively modulates Armcx3 expression, which is implicated in mitochondrial transport. Prx II deficiency reduces Armcx3 levels via this pathway in neuronal (HT22) cells.\",\n      \"method\": \"RNA sequencing, Prx II knockdown/overexpression in HT22 cells, bioinformatic pathway analysis, miR-181b-5p target validation\",\n      \"journal\": \"Cell Communication and Signaling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily transcriptomic/bioinformatic with limited direct mechanistic validation of the axis for ARMCX3 specifically\",\n      \"pmids\": [\"38637880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ARMCX3 knockdown in dental pulp stem cells (hDPSCs) accelerates neural differentiation and reduces inflammatory cytokine levels under LPS-induced inflammation. ARMCX3 overexpression increases ROS production, and ROS inhibition reverses the effects of ARMCX3 overexpression, indicating ARMCX3 regulates neural differentiation and inflammation at least partly through ROS signaling.\",\n      \"method\": \"Lentiviral knockdown and overexpression in hDPSCs, ROS measurement (specific kits), immunofluorescence, qRT-PCR, ELISA, ROS inhibitor rescue experiment\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, gain/loss-of-function with pharmacological rescue; mechanism upstream of ROS not defined\",\n      \"pmids\": [\"39296219\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARMCX3 (Alex3) is a Eutherian-specific integral membrane protein of the mitochondrial outer membrane that forms a Ca2+-sensitive complex with Miro1/Trak2 and Kinesin motors to control mitochondrial trafficking and dynamics in neurons; it further interacts with Gαq to transduce GPCR signals to the mitochondrial transport machinery independently of PLCβ, is subject to degradation via the non-canonical Wnt/PKC pathway, interacts with Sox10 to potentiate transcriptional activity, and interacts with SOX9 to promote hepatic cell proliferation, with loss of ARMCX3 causing neuronal death, motor deficits, and protection from hepatocarcinogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARMCX3 (Alex3) is an integral membrane protein of the mitochondrial outer membrane that controls mitochondrial dynamics and trafficking, particularly in neurons [#0, #1]. It assembles into the Kinesin/Miro1/Trak2 motor adaptor complex in a Ca2+-dependent manner, positioning it as a regulator of mitochondrial movement [#0], and it further recruits Gαq into this complex to transduce GPCR signals onto the transport machinery independently of the canonical PLCβ pathway; CNS-specific loss of ARMCX3 abolishes Gαq-mediated control of mitochondrial trafficking and dendritic growth and causes ER stress, neuronal and motor neuron death, and severe motor deficits [#7]. ARMCX3 protein stability is regulated by the non-canonical Wnt/PKC pathway, which drives its degradation and thereby modulates mitochondrial morphology [#2]. Beyond its trafficking role, ARMCX3 interacts with the transcription factors Sox10 and SOX9: it binds Sox10 at the outer mitochondrial membrane and potentiates Sox10-dependent transactivation without intrinsic transcriptional activity [#1], and its interaction with SOX9 drives hepatic cell proliferation, with ARMCX3 knockout protecting mice against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis [#5]. ARMCX3 also acts as a negative regulator of white adipose tissue browning and mitochondrial oxidative activity, with its expression repressed by thermogenic stimulation and induced by obesity [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established the first molecular partner of ARMCX3 by showing it is an outer mitochondrial membrane protein that binds the transcription factor Sox10 and potentiates Sox10-driven transcription, linking a mitochondrial protein to gene regulation.\",\n      \"evidence\": \"Co-IP, membrane fractionation, and luciferase reporter assays in neuronal-like cell lines\",\n      \"pmids\": [\"19304657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which a membrane-anchored protein influences nuclear transactivation not defined\", \"Single-lab interaction without reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined ARMCX3's core cellular function by placing it within the Kinesin/Miro/Trak2 motor adaptor complex and showing Ca2+-dependent regulation of mitochondrial trafficking in neurons.\",\n      \"evidence\": \"Subcellular fractionation, reciprocal Co-IP with Miro and Trak2, live-imaging of mitochondrial trafficking with overexpression/knockdown\",\n      \"pmids\": [\"22569362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Ca2+ sensing within the complex unresolved\", \"Did not address upstream signals controlling complex assembly\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified an upstream regulatory input controlling ARMCX3 by showing the non-canonical Wnt/PKC pathway degrades the protein and thereby modulates mitochondrial morphology.\",\n      \"evidence\": \"Wnt treatment and PKC pharmacological inhibition with immunoblot and mitochondrial morphology readout in HEK293 cells\",\n      \"pmids\": [\"23844091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific E3 ligase/degradation machinery not identified\", \"Performed in non-neuronal overexpression system\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected ARMCX3's mitochondrial localization to developmental phenotypes, showing it regulates neural progenitor proliferation and inhibits Wnt-β-catenin signaling in a localization-dependent manner.\",\n      \"evidence\": \"In ovo electroporation of knockdown/overexpression and localization mutants in chick neural tube with proliferation and differentiation markers\",\n      \"pmids\": [\"26973462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between mitochondrial anchoring and Wnt inhibition not defined\", \"Single in vivo model\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended ARMCX3 function to disease pathophysiology by demonstrating it drives hepatic tumorigenesis under lipotoxicity through a SOX9 interaction, with knockout being protective.\",\n      \"evidence\": \"Inducible ARMCX3 KO mouse with high-fat-diet/diethylnitrosamine carcinogenesis, HCC cell line gain/loss-of-function, and Co-IP for SOX9\",\n      \"pmids\": [\"33807672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How mitochondrial ARMCX3 engages the SOX9 transcriptional program mechanistically unclear\", \"Relationship between the Sox10 and SOX9 interactions not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a metabolic role for ARMCX3 as a negative regulator of adipose browning and mitochondrial oxidative activity responsive to thermogenic and obesogenic signals.\",\n      \"evidence\": \"Armcx3 KO mice, adenoviral overexpression and siRNA in brown adipocytes, qPCR, mitochondrial respiration assays, histology\",\n      \"pmids\": [\"35705702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular effectors of thermogenic gene repression not identified\", \"Link to its motor-complex function in adipocytes unexplored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Integrated ARMCX3 into GPCR signaling by showing it recruits Gαq to the Miro1/Trak2 complex to arrest mitochondrial transport independently of PLCβ, with conditional knockout producing severe neurodegenerative phenotypes.\",\n      \"evidence\": \"Mitoproteome mass spectrometry, Co-IP, CNS-specific conditional KO mouse, live-imaging of trafficking, dendritic and histological analyses\",\n      \"pmids\": [\"38320000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism by which Gαq engagement halts the motor not resolved\", \"Receptors upstream of the Gαq input not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed transcriptional/post-transcriptional control of Armcx3 expression via a Prx II–ATF3–miR-181b-5p axis affecting mitochondrial transport.\",\n      \"evidence\": \"RNA-seq, Prx II knockdown/overexpression in HT22 cells, bioinformatics, miR-181b-5p target validation\",\n      \"pmids\": [\"38637880\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Primarily transcriptomic/bioinformatic with limited direct validation for ARMCX3\", \"Causal contribution of each node to ARMCX3 function untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked ARMCX3 to ROS signaling in regulating neural differentiation and inflammation in dental pulp stem cells.\",\n      \"evidence\": \"Lentiviral knockdown/overexpression in hDPSCs with ROS measurement and ROS-inhibitor rescue, qRT-PCR, ELISA\",\n      \"pmids\": [\"39296219\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanism upstream of ROS not defined\", \"Single-lab gain/loss-of-function without genetic rescue\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ARMCX3's dual roles — as a mitochondrial motor adaptor and as a partner of transcription factors (Sox10, SOX9) — are mechanistically coordinated, and what the structural basis of its Ca2+- and Gαq-dependent control of the Miro1/Trak2 complex is, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the ARMCX3/Miro1/Trak2/Gαq complex\", \"Mechanism connecting mitochondrial anchoring to transcriptional partner regulation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [\"Miro1/Trak2/Kinesin motor adaptor complex\"],\n    \"partners\": [\"MIRO1\", \"TRAK2\", \"GNAQ\", \"SOX10\", \"SOX9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}