{"gene":"ARMC1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2019,"finding":"ARMC1 localizes to both the cytosol and mitochondria, where it associates with the outer mitochondrial membrane through its carboxy-terminus, and interacts with components of the MICOS/MIB (mitochondrial intermembrane space bridging) complex. Mitochondria lacking ArmC1 appear fragmented and show reduced motility, but do not show defects in cristae structure, respiration, or protein content, indicating ArmC1 is a peripheral MICOS/MIB component with a role in mitochondrial distribution.","method":"Subcellular fractionation, Co-immunoprecipitation, loss-of-function (knockdown/knockout) with live-cell imaging and functional readouts (cristae morphology, respiration, mitochondrial motility)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and direct localization with functional consequence (fragmentation, motility), single lab, multiple orthogonal methods","pmids":["31644573"],"is_preprint":false},{"year":2025,"finding":"ARMC1 partitions between two distinct mitochondrial protein complexes: (1) a MIRO-ARMC1-MTFR complex, where MIRO recruits ARMC1 which mediates assembly and stability of mitochondrial fission regulator MTFR, and this complex specifically antagonizes retrograde mitochondrial movement; and (2) a complex with DNAJC11, which facilitates ARMC1 release from mitochondria. ARMC1 deletion causes perinuclear mitochondrial clustering that cannot be rescued by disrupting MIRO-MTFR assembly alone, while disrupting the ARMC1-DNAJC11 interaction leads to excessive mitochondrially localized ARMC1 and distinct mitochondrial defects. Thus, ARMC1 mito-cytoplasmic shuttling balanced by DNAJC11 tunes steady-state mitochondrial distributions.","method":"Co-immunoprecipitation, ARMC1 deletion with defined phenotypic readouts (perinuclear clustering), epistasis by disrupting specific protein-protein interactions (MIRO-MTFR assembly, ARMC1-DNAJC11 interaction), protein stability assays (MTFR stability dependent on ARMC1)","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, KO, epistasis, stability assays), clear mechanistic dissection of two distinct complexes and functional consequences in a single rigorous study","pmids":["40203102"],"is_preprint":false},{"year":2025,"finding":"MSC-conditioned media upregulates ARMC1 protein in TGF-β1-treated kidney cells and in adenine-induced nephropathy mouse renal tissue. ARMC1 overexpression reduces DRP1 (a fission regulator) and enhances OPA1 and MFN2 (fusion regulators), lowers ROS, and boosts mitochondrial bioactivity, suggesting ARMC1 inhibits mitochondrial fission and reduces oxidative stress. ARMC1 overexpression also decreases fibrosis markers and raises antioxidant proteins (NRF2, SOD1, SOD2, CAT).","method":"ARMC1 overexpression (lentiviral vector) in HK-2 cells with measurement of mitochondrial dynamics proteins (DRP1, OPA1, MFN2), ROS levels, antioxidant proteins, and fibrosis markers; renal proteomics in mouse model","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — overexpression with multiple functional readouts (protein levels, ROS, fibrosis markers), single lab, but no direct mechanistic epistasis establishing how ARMC1 regulates DRP1","pmids":["41153008"],"is_preprint":false},{"year":2019,"finding":"In C. elegans, the ARCP-1 protein (ortholog of ARMC1) is a polymorphic dendritic scaffold protein expressed in sensory neurons that binds the Ca2+-dependent phosphodiesterase PDE-1 and co-localizes PDE-1 with molecular sensors for CO2 at dendritic ends. Reducing ARCP-1 or PDE-1 activity promotes CO2 escape by altering neuropeptide expression in BAG CO2 sensors. Variation in ARCP-1 alters behavioral plasticity in multiple paradigms.","method":"Genetic mapping, co-localization (live imaging), loss-of-function with behavioral readouts (CO2 escape), neuropeptide expression analysis","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding partner identified (PDE-1), co-localization at dendritic ends, loss-of-function with defined cellular/behavioral phenotype; C. elegans ortholog, single lab","pmids":["31757604"],"is_preprint":false}],"current_model":"ARMC1 is a dual-localization (cytosol and mitochondria) armadillo repeat-containing scaffold protein that partitions between distinct mitochondrial complexes: it is recruited by the trafficking adaptor MIRO to mediate assembly and stabilization of the fission regulator MTFR (antagonizing retrograde mitochondrial movement), while DNAJC11 facilitates its release from mitochondria; this mito-cytoplasmic shuttling balanced by DNAJC11 tunes steady-state mitochondrial distribution, and ARMC1 is also a peripheral component of the MICOS/MIB complex with a role in mitochondrial morphology and motility."},"narrative":{"mechanistic_narrative":"ARMC1 is a dual-localized armadillo repeat-containing scaffold protein that partitions between the cytosol and the outer mitochondrial membrane to govern mitochondrial distribution and motility [PMID:31644573, PMID:40203102]. It associates with the outer membrane through its carboxy-terminus and behaves as a peripheral component of the MICOS/MIB complex; its loss fragments mitochondria and reduces their motility without disrupting cristae architecture, respiration, or protein content [PMID:31644573]. Mechanistically, ARMC1 partitions between two distinct mitochondrial complexes: it is recruited by the trafficking adaptor MIRO into a MIRO–ARMC1–MTFR complex in which ARMC1 mediates assembly and stability of the fission regulator MTFR and antagonizes retrograde mitochondrial movement, while a separate interaction with DNAJC11 facilitates ARMC1 release from mitochondria [PMID:40203102]. This DNAJC11-balanced mito-cytoplasmic shuttling sets steady-state mitochondrial positioning, such that ARMC1 deletion causes perinuclear mitochondrial clustering not rescued by disrupting MIRO–MTFR assembly alone, and disruption of the ARMC1–DNAJC11 interaction produces excess mitochondrial ARMC1 with distinct defects [PMID:40203102]. Consistent with a role in mitochondrial dynamics, ARMC1 overexpression shifts the fission/fusion balance toward fusion (lowering DRP1, raising OPA1 and MFN2), reduces ROS, and elevates antioxidant proteins in a kidney-cell injury model [PMID:41153008]. The C. elegans ortholog ARCP-1 acts as a dendritic scaffold that binds the phosphodiesterase PDE-1 and positions it with CO2 sensors in sensory neurons, shaping behavioral plasticity [PMID:31757604].","teleology":[{"year":2019,"claim":"Establishing where ARMC1 acts and what it does answered whether this armadillo protein is a mitochondrial factor and defined its first functional role in organelle distribution.","evidence":"Subcellular fractionation, reciprocal Co-IP with MICOS/MIB components, and loss-of-function with live-cell imaging in cultured cells","pmids":["31644573"],"confidence":"Medium","gaps":["Did not define how ARMC1 mechanistically controls mitochondrial motility","Role as a peripheral MICOS/MIB component not linked to any enzymatic or assembly activity","No partner shown to recruit ARMC1 to the membrane"]},{"year":2019,"claim":"Characterizing the C. elegans ortholog ARCP-1 revealed a conserved scaffolding logic, showing the protein can spatially organize a signaling enzyme at a defined cellular site.","evidence":"Genetic mapping, live-imaging co-localization, and loss-of-function with behavioral and neuropeptide readouts in C. elegans sensory neurons","pmids":["31757604"],"confidence":"Medium","gaps":["PDE-1 binding and dendritic scaffolding role not shown to translate to mammalian ARMC1","Relationship between neuronal scaffolding function and mitochondrial function unresolved","Single-organism ortholog evidence"]},{"year":2025,"claim":"Dissecting two distinct ARMC1-containing complexes answered how ARMC1 controls mitochondrial positioning, establishing a MIRO-recruited, MTFR-stabilizing module antagonizing retrograde movement and a DNAJC11-dependent release mechanism that tunes shuttling.","evidence":"Co-IP, ARMC1 knockout with perinuclear-clustering phenotyping, epistasis by selectively disrupting MIRO-MTFR and ARMC1-DNAJC11 interactions, and MTFR protein-stability assays","pmids":["40203102"],"confidence":"High","gaps":["Molecular trigger that switches ARMC1 between the MIRO-MTFR and DNAJC11 complexes is unknown","Structural basis of ARMC1-mediated MTFR assembly/stabilization not resolved","Mechanism by which DNAJC11 drives ARMC1 release from mitochondria not defined"]},{"year":2025,"claim":"Linking ARMC1 to fission/fusion balance and oxidative stress connected its scaffolding function to a tissue-level injury context.","evidence":"Lentiviral ARMC1 overexpression in HK-2 cells with measurement of DRP1/OPA1/MFN2, ROS, antioxidant and fibrosis markers, plus renal proteomics in an adenine-nephropathy mouse model","pmids":["41153008"],"confidence":"Medium","gaps":["No epistasis establishing how ARMC1 lowers DRP1 or raises fusion regulators","Causality between ARMC1 and antioxidant/fibrosis changes is correlative","Overexpression-based; physiological relevance of endogenous ARMC1 in kidney not tested"]},{"year":null,"claim":"How ARMC1's biochemical activity (armadillo-repeat scaffolding) drives complex assembly remains undefined at the structural and switching level.","evidence":"No structural or reconstitution study in the available corpus addresses the molecular switch between mitochondrial and cytosolic ARMC1 pools.","pmids":[],"confidence":"High","gaps":["No structure of ARMC1 or its complexes","Signal controlling MIRO-MTFR versus DNAJC11 partitioning unknown","Whether neuronal scaffolding and mitochondrial roles share a common biochemical mechanism is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1]}],"complexes":["MICOS/MIB","MIRO-ARMC1-MTFR"],"partners":["MIRO","MTFR","DNAJC11","PDE-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NVT9","full_name":"Armadillo repeat-containing protein 1","aliases":[],"length_aa":282,"mass_kda":31.3,"function":"In association with mitochondrial contact site and cristae organizing system (MICOS) complex components and mitochondrial outer membrane sorting assembly machinery (SAM) complex components may regulate mitochondrial dynamics playing a role in determining mitochondrial length, distribution and motility","subcellular_location":"Cytoplasm; Mitochondrion; Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q9NVT9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARMC1","classification":"Not 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all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ARMC1"},"hgnc":{"alias_symbol":["FLJ10511","Arcp"],"prev_symbol":[]},"alphafold":{"accession":"Q9NVT9","domains":[{"cath_id":"-","chopping":"13-111","consensus_level":"high","plddt":93.3662,"start":13,"end":111},{"cath_id":"3.30.70.100","chopping":"141-222","consensus_level":"high","plddt":91.8689,"start":141,"end":222}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVT9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVT9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVT9-F1-predicted_aligned_error_v6.png","plddt_mean":78.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARMC1","jax_strain_url":"https://www.jax.org/strain/search?query=ARMC1"},"sequence":{"accession":"Q9NVT9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NVT9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NVT9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVT9"}},"corpus_meta":[{"pmid":"9484229","id":"PMC_9484229","title":"Characterization 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Mitochondria lacking ArmC1 appear fragmented and show reduced motility, but do not show defects in cristae structure, respiration, or protein content, indicating ArmC1 is a peripheral MICOS/MIB component with a role in mitochondrial distribution.\",\n      \"method\": \"Subcellular fractionation, Co-immunoprecipitation, loss-of-function (knockdown/knockout) with live-cell imaging and functional readouts (cristae morphology, respiration, mitochondrial motility)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and direct localization with functional consequence (fragmentation, motility), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31644573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ARMC1 partitions between two distinct mitochondrial protein complexes: (1) a MIRO-ARMC1-MTFR complex, where MIRO recruits ARMC1 which mediates assembly and stability of mitochondrial fission regulator MTFR, and this complex specifically antagonizes retrograde mitochondrial movement; and (2) a complex with DNAJC11, which facilitates ARMC1 release from mitochondria. ARMC1 deletion causes perinuclear mitochondrial clustering that cannot be rescued by disrupting MIRO-MTFR assembly alone, while disrupting the ARMC1-DNAJC11 interaction leads to excessive mitochondrially localized ARMC1 and distinct mitochondrial defects. Thus, ARMC1 mito-cytoplasmic shuttling balanced by DNAJC11 tunes steady-state mitochondrial distributions.\",\n      \"method\": \"Co-immunoprecipitation, ARMC1 deletion with defined phenotypic readouts (perinuclear clustering), epistasis by disrupting specific protein-protein interactions (MIRO-MTFR assembly, ARMC1-DNAJC11 interaction), protein stability assays (MTFR stability dependent on ARMC1)\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, KO, epistasis, stability assays), clear mechanistic dissection of two distinct complexes and functional consequences in a single rigorous study\",\n      \"pmids\": [\"40203102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MSC-conditioned media upregulates ARMC1 protein in TGF-β1-treated kidney cells and in adenine-induced nephropathy mouse renal tissue. ARMC1 overexpression reduces DRP1 (a fission regulator) and enhances OPA1 and MFN2 (fusion regulators), lowers ROS, and boosts mitochondrial bioactivity, suggesting ARMC1 inhibits mitochondrial fission and reduces oxidative stress. ARMC1 overexpression also decreases fibrosis markers and raises antioxidant proteins (NRF2, SOD1, SOD2, CAT).\",\n      \"method\": \"ARMC1 overexpression (lentiviral vector) in HK-2 cells with measurement of mitochondrial dynamics proteins (DRP1, OPA1, MFN2), ROS levels, antioxidant proteins, and fibrosis markers; renal proteomics in mouse model\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — overexpression with multiple functional readouts (protein levels, ROS, fibrosis markers), single lab, but no direct mechanistic epistasis establishing how ARMC1 regulates DRP1\",\n      \"pmids\": [\"41153008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In C. elegans, the ARCP-1 protein (ortholog of ARMC1) is a polymorphic dendritic scaffold protein expressed in sensory neurons that binds the Ca2+-dependent phosphodiesterase PDE-1 and co-localizes PDE-1 with molecular sensors for CO2 at dendritic ends. Reducing ARCP-1 or PDE-1 activity promotes CO2 escape by altering neuropeptide expression in BAG CO2 sensors. Variation in ARCP-1 alters behavioral plasticity in multiple paradigms.\",\n      \"method\": \"Genetic mapping, co-localization (live imaging), loss-of-function with behavioral readouts (CO2 escape), neuropeptide expression analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding partner identified (PDE-1), co-localization at dendritic ends, loss-of-function with defined cellular/behavioral phenotype; C. elegans ortholog, single lab\",\n      \"pmids\": [\"31757604\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARMC1 is a dual-localization (cytosol and mitochondria) armadillo repeat-containing scaffold protein that partitions between distinct mitochondrial complexes: it is recruited by the trafficking adaptor MIRO to mediate assembly and stabilization of the fission regulator MTFR (antagonizing retrograde mitochondrial movement), while DNAJC11 facilitates its release from mitochondria; this mito-cytoplasmic shuttling balanced by DNAJC11 tunes steady-state mitochondrial distribution, and ARMC1 is also a peripheral component of the MICOS/MIB complex with a role in mitochondrial morphology and motility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARMC1 is a dual-localized armadillo repeat-containing scaffold protein that partitions between the cytosol and the outer mitochondrial membrane to govern mitochondrial distribution and motility [#0, #1]. It associates with the outer membrane through its carboxy-terminus and behaves as a peripheral component of the MICOS/MIB complex; its loss fragments mitochondria and reduces their motility without disrupting cristae architecture, respiration, or protein content [#0]. Mechanistically, ARMC1 partitions between two distinct mitochondrial complexes: it is recruited by the trafficking adaptor MIRO into a MIRO–ARMC1–MTFR complex in which ARMC1 mediates assembly and stability of the fission regulator MTFR and antagonizes retrograde mitochondrial movement, while a separate interaction with DNAJC11 facilitates ARMC1 release from mitochondria [#1]. This DNAJC11-balanced mito-cytoplasmic shuttling sets steady-state mitochondrial positioning, such that ARMC1 deletion causes perinuclear mitochondrial clustering not rescued by disrupting MIRO–MTFR assembly alone, and disruption of the ARMC1–DNAJC11 interaction produces excess mitochondrial ARMC1 with distinct defects [#1]. Consistent with a role in mitochondrial dynamics, ARMC1 overexpression shifts the fission/fusion balance toward fusion (lowering DRP1, raising OPA1 and MFN2), reduces ROS, and elevates antioxidant proteins in a kidney-cell injury model [#2]. The C. elegans ortholog ARCP-1 acts as a dendritic scaffold that binds the phosphodiesterase PDE-1 and positions it with CO2 sensors in sensory neurons, shaping behavioral plasticity [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing where ARMC1 acts and what it does answered whether this armadillo protein is a mitochondrial factor and defined its first functional role in organelle distribution.\",\n      \"evidence\": \"Subcellular fractionation, reciprocal Co-IP with MICOS/MIB components, and loss-of-function with live-cell imaging in cultured cells\",\n      \"pmids\": [\"31644573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Did not define how ARMC1 mechanistically controls mitochondrial motility\",\n        \"Role as a peripheral MICOS/MIB component not linked to any enzymatic or assembly activity\",\n        \"No partner shown to recruit ARMC1 to the membrane\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Characterizing the C. elegans ortholog ARCP-1 revealed a conserved scaffolding logic, showing the protein can spatially organize a signaling enzyme at a defined cellular site.\",\n      \"evidence\": \"Genetic mapping, live-imaging co-localization, and loss-of-function with behavioral and neuropeptide readouts in C. elegans sensory neurons\",\n      \"pmids\": [\"31757604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"PDE-1 binding and dendritic scaffolding role not shown to translate to mammalian ARMC1\",\n        \"Relationship between neuronal scaffolding function and mitochondrial function unresolved\",\n        \"Single-organism ortholog evidence\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Dissecting two distinct ARMC1-containing complexes answered how ARMC1 controls mitochondrial positioning, establishing a MIRO-recruited, MTFR-stabilizing module antagonizing retrograde movement and a DNAJC11-dependent release mechanism that tunes shuttling.\",\n      \"evidence\": \"Co-IP, ARMC1 knockout with perinuclear-clustering phenotyping, epistasis by selectively disrupting MIRO-MTFR and ARMC1-DNAJC11 interactions, and MTFR protein-stability assays\",\n      \"pmids\": [\"40203102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular trigger that switches ARMC1 between the MIRO-MTFR and DNAJC11 complexes is unknown\",\n        \"Structural basis of ARMC1-mediated MTFR assembly/stabilization not resolved\",\n        \"Mechanism by which DNAJC11 drives ARMC1 release from mitochondria not defined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linking ARMC1 to fission/fusion balance and oxidative stress connected its scaffolding function to a tissue-level injury context.\",\n      \"evidence\": \"Lentiviral ARMC1 overexpression in HK-2 cells with measurement of DRP1/OPA1/MFN2, ROS, antioxidant and fibrosis markers, plus renal proteomics in an adenine-nephropathy mouse model\",\n      \"pmids\": [\"41153008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No epistasis establishing how ARMC1 lowers DRP1 or raises fusion regulators\",\n        \"Causality between ARMC1 and antioxidant/fibrosis changes is correlative\",\n        \"Overexpression-based; physiological relevance of endogenous ARMC1 in kidney not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ARMC1's biochemical activity (armadillo-repeat scaffolding) drives complex assembly remains undefined at the structural and switching level.\",\n      \"evidence\": \"No structural or reconstitution study in the available corpus addresses the molecular switch between mitochondrial and cytosolic ARMC1 pools.\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of ARMC1 or its complexes\",\n        \"Signal controlling MIRO-MTFR versus DNAJC11 partitioning unknown\",\n        \"Whether neuronal scaffolding and mitochondrial roles share a common biochemical mechanism is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"MICOS/MIB\", \"MIRO-ARMC1-MTFR\"],\n    \"partners\": [\"MIRO\", \"MTFR\", \"DNAJC11\", \"PDE-1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}