{"gene":"IMMT","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1996,"finding":"Mitofilin (IMMT/HMP) is a mitochondrial inner membrane protein that resides predominantly in the intermembrane space, contains predicted coiled-coil domains, is resistant to detergent extraction, co-purifies with mitochondria, and is not co-localized with Golgi or ER. Limited proteolysis and immuno-electron microscopy confirmed its intermembrane space localization at the mitochondrial periphery.","method":"Subcellular fractionation, immunofluorescence, immunoelectron microscopy, limited proteolysis, Western blotting","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, IEM, proteolysis, co-localization studies) in a single focused characterization paper; foundational localization and domain study","pmids":["8886976"],"is_preprint":false},{"year":2015,"finding":"Mic60/Mitofilin is a core scaffold for MICOS complex assembly: knockdown of Mic60 causes instability of other MICOS components and disassembly of the complex. Mic60 directly interacts with Mic19/CHCHD3, and this interaction is required for their mutual stabilization. Disrupted MICOS assembly causes giant mitochondria formation due to dysregulated fission/fusion, and mtDNA nucleoids become clustered and transcription is attenuated. The mitochondrial i-AAA protease Yme1L regulates Mic60 homeostasis.","method":"shRNA knockdown, co-immunoprecipitation, Western blotting, immunofluorescence, electron microscopy, mtDNA transcription assay","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, KD with multiple defined phenotypic readouts (MICOS disassembly, mitochondrial morphology, mtDNA transcription), and protease identification in single focused study","pmids":["26250910"],"is_preprint":false},{"year":2016,"finding":"MIC60 physically interacts with OPA1, and together they control cristae junction number and stability. OPA1 is epistatic to MIC60 in cristae shape regulation: OPA1 defines cristae width and junction diameter independently of MIC60, while both are components of high-molecular-weight complexes disrupted during cristae remodeling. MIC60 is a core MICOS protein required for normal cristae junction formation.","method":"Proteomics of native complexes, co-immunoprecipitation, genetic epistasis (double KD), electron tomography, biochemistry","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, epistasis genetics, electron tomography with multiple orthogonal methods in single study","pmids":["27974214"],"is_preprint":false},{"year":2016,"finding":"PKA phosphorylates MIC60 at Ser528. MIC60 transiently interacts with PINK1. MIC60 downregulation reduces PINK1 protein levels and causes mislocalization of Parkin. Phosphorylation-mimic MIC60 (Ser528Asp) fails to restore Parkin recruitment in MIC60-knockdown cells, while phosphorylation-deficient MIC60 (Ser528Ala) facilitates mitochondrial Parkin localization. Thus PKA-mediated phosphorylation of MIC60 negatively regulates the PINK1-Parkin mitophagy pathway.","method":"Mutational analysis, mass spectrometry, co-immunoprecipitation, shRNA knockdown, fluorescence microscopy","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometric identification of phosphosite, mutagenesis of phosphosite with functional rescue, Co-IP for PINK1 interaction; single lab but multiple orthogonal methods","pmids":["27153535"],"is_preprint":false},{"year":2018,"finding":"PINK1 phosphorylates the inner mitochondrial membrane protein MIC60/mitofilin in Drosophila and human neurons. PINK1-dependent phosphorylation stabilizes MIC60 oligomerization and promotes crista junction formation. Expression of MIC60 rescues crista structure, ATP levels, behavioral defects, and dopaminergic neurodegeneration in PINK1-null Drosophila. MIC60 coding variants in the mitochondrial targeting sequence found in PD patients impair crista junction formation in Drosophila.","method":"In vivo Drosophila genetics, biochemical reconstitution of phosphorylation, MIC60 oligomerization assay, electron microscopy of crista junctions, rescue experiments, human neuron studies","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct kinase-substrate relationship with in vivo rescue, oligomerization assay, electron microscopy, cross-species validation (Drosophila and human neurons)","pmids":["29456190"],"is_preprint":false},{"year":2015,"finding":"Mic60 interacts with mitochondrial transcription factors TFAM and TFB2M. Mic60 knockdown compromises mitochondrial transcription and OXPHOS activities, decreases TFAM binding and POLRMT recruitment to mtDNA promoters. Mic60 interacts with mtDNA and is involved in the architecture of the mtDNA D-loop region, as shown by mtDNA immunoprecipitation and 3C assays.","method":"Co-immunoprecipitation, shRNA knockdown, ChIP on mtDNA, mIP-3C assay, OXPHOS activity measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with transcription factors, KD with functional readouts, novel mtDNA-3C assay; single lab","pmids":["25612828"],"is_preprint":false},{"year":2019,"finding":"Mic19 directly interacts with both Sam50 (outer membrane SAM complex) and Mic60 (MICOS complex) to form a Sam50-Mic19-Mic60 axis that integrates SAM and MICOS into the MIB (mitochondrial intermembrane space bridging) supercomplex, mediating outer- and inner-membrane contact. OMA1-mediated cleavage of Mic19 disrupts this axis, causing MIB disassembly, loss of cristae junctions, and reduced ATP production. Sam50 acts as an anchoring point guiding cristae junction formation at the outer membrane.","method":"Co-immunoprecipitation, pulldown, knockdown, super-resolution microscopy, electron microscopy, ATP production assay","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing ternary complex, OMA1 cleavage mechanistic dissection, KD with defined phenotypic readouts across multiple methods in single focused study","pmids":["31097788"],"is_preprint":false},{"year":2017,"finding":"Mic19, Mic60, and Sam50 localize specifically to crista junctions in a network pattern along the mitochondrial periphery, with enrichment also inside cristae, as determined by miniSOG and APEX2 genetic tags and electron tomography at nanoscale resolution. Sam50 is not uniformly distributed in the outer mitochondrial membrane and incompletely overlaps with Mic19/Mic60 at crista junctions.","method":"Genetically encoded electron microscopy tags (miniSOG, APEX2), electron tomography, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — nanoscale electron tomography with genetic tags; novel high-resolution localization with functional context in single lab study","pmids":["28808085"],"is_preprint":false},{"year":2017,"finding":"Drosophila MIC60 performs dual functions: (1) maintenance of crista membrane structure (canonical role) and (2) regulation of mitochondrial motility by influencing protein levels of the outer mitochondrial membrane protein Miro that anchors mitochondria to microtubule motors. Loss of MIC60 causes loss of Miro and mitochondrial arrest, and disrupts synaptic structure and function at neuromuscular junctions.","method":"Drosophila genetic mutant analysis, Western blotting, mitochondrial motility assays, neuromuscular junction imaging, electron microscopy","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function genetics with defined phenotypic readouts (motility, Miro levels, NMJ structure); single lab, Drosophila model","pmids":["28904209"],"is_preprint":false},{"year":2023,"finding":"MARCH5 acts as an E3 ubiquitin ligase that specifically targets MIC60, mediating K48-linked ubiquitination at Lys285 to promote its degradation under high glucose/palmitate (diabetic) conditions. TRAP1 inhibits MARCH5-mediated ubiquitination by competitively binding to MIC60. Mutation of the MIC60 ubiquitination site (Lys285) or the MIC60-interacting motifs in MARCH5 abrogates MARCH5-mediated MIC60 ubiquitination and degradation.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, mass spectrometry, shRNA knockdown, overexpression","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-specific ubiquitination mapped by mutagenesis and mass spectrometry, competitive binding assay, functional rescue; single lab but multiple orthogonal methods","pmids":["37679468"],"is_preprint":false},{"year":2021,"finding":"TRAP1 mitigates extracellular acidosis-induced mitochondrial impairment and cardiac injury by directly interacting with MIC60 to decrease its ubiquitin-dependent degradation. Overexpression of MIC60 in acidosis maintains cell viability, increases ATP production, mitochondrial membrane potential, and mitigates disruption of mitochondrial structure.","method":"Co-immunoprecipitation, overexpression, shRNA knockdown, mitochondrial membrane potential assay, ATP measurement","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for TRAP1-MIC60 interaction, KD/OE with functional readouts; single lab","pmids":["34907169"],"is_preprint":false},{"year":2023,"finding":"MDM2 acts as an E3 ubiquitin ligase that increases MIC60 ubiquitination, causing its degradation, which impairs mitophagy and induces autophagosome overaccumulation and microglial inflammation. MDM2 silencing significantly attenuates mitochondrial damage caused by ZnO-NPs by preventing MIC60 ubiquitination and degradation.","method":"In vivo mouse model, in vitro ZnO-NP exposure, siRNA knockdown, ubiquitination assay, mitophagy assay, immunofluorescence","journal":"Journal of hazardous materials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identification of MDM2 as E3 ligase with functional rescue via silencing; single lab, in vivo and in vitro","pmids":["37315416"],"is_preprint":false},{"year":2024,"finding":"Tamoxifen-inducible deletion of Immt in adult mice disrupts the MICOS complex, increases mitochondrial size, alters cristae morphology, and is lethal within 12 days, demonstrating that MIC60 is essential for MICOS integrity in vivo. Pathological consequences include defective intestinal muscle function (paralytic ileus) and bone marrow hypocellularity.","method":"Conditional knockout mouse model (ROSA-CreERT2), electron microscopy, Western blotting, pathological analysis","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous conditional KO mouse model with defined molecular (MICOS disruption) and organismal phenotypic consequences; in vivo genetic ablation","pmids":["38467404"],"is_preprint":false},{"year":2020,"finding":"MIC60 was identified as the direct binding target of the small molecule miclxin using drug-immobilized affinity beads. MIC60 dysfunction caused by miclxin induces a mitochondrial stress response in a mutant β-catenin-dependent manner, leading to Bcl-2 downregulation, loss of mitochondrial membrane potential, and apoptosis-inducing factor-dependent apoptosis.","method":"Affinity bead pulldown (drug-immobilized beads), Western blotting, flow cytometry, cell death assays","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct drug-affinity pulldown identifying MIC60 as target, functional consequences of MIC60 inhibition established; single lab","pmids":["32584541"],"is_preprint":false},{"year":2016,"finding":"Mic60/mitofilin overexpression in dopaminergic neuronal cells attenuates dopamine- and rotenone-induced cell death, increases mitochondrial respiration and spare respiratory capacity, suppresses mitochondrial fission, and increases mitochondrial length in neurites. Mic60 knockdown potentiates dopamine-induced cell death and suppresses respiration, demonstrating that Mic60 controls both mitochondrial membrane function and fission/fusion dynamics in neurons.","method":"shRNA knockdown, overexpression, Seahorse respirometry, mitochondrial imaging, cell death assays in differentiated SH-SY5Y and PC12 cells and primary rat cortical neurons","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with multiple functional readouts (respiration, morphology, cell death); single lab, multiple cell models","pmids":["27001148"],"is_preprint":false},{"year":2023,"finding":"Alphaproteobacterial Mic60 (ortholog of eukaryotic IMMT/Mic60) physically interacts with BamA, the homolog of Sam50, recapitulating the conserved Mic60-Sam50 interaction from bacteria to mitochondria. Disruption of Mic60 and adjacent gene Orf52 in Rhodobacter sphaeroides and Rhodopseudomonas palustris causes photoheterotrophic growth defects and enlarged intracytoplasmic membranes (ICMs), supporting a role in ICM/crista organization.","method":"Genetic disruption, overexpression, physical interaction assay, electron microscopy, photoheterotrophic growth assays","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct physical interaction demonstrated for BamA-Mic60 in bacteria, genetic loss-of-function with ICM phenotype; single lab, bacterial ortholog","pmids":["36921606"],"is_preprint":false},{"year":2021,"finding":"Homozygous pathogenic variants (c.895A>G, p.Lys299Glu) in IMMT cause mitochondrial developmental encephalopathy with optic neuropathy in humans. Functional studies showed that loss of IMMT function causes alterations in mitochondrial cristae morphology, confirming the essential role of IMMT/mitofilin in cristae organization in vivo.","method":"Clinical genetics, Sanger sequencing, electron microscopy of patient mitochondria, co-segregation analysis","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human disease-causing variant with electron microscopy confirmation of cristae defect; single family/case but direct functional validation","pmids":["34842280"],"is_preprint":false},{"year":2025,"finding":"Lactylation of Mic60 protein is a critical post-translational modification that affects mitochondrial cristae remodeling and activates mitochondrial metabolism. Dysfunction of DAPK2 kinase alters Mic60 protein in mitochondrial cristae, increasing cristae abundance and compactness and activating mitochondrial metabolism, contributing to EGFR-TKI resistance and cancer metastasis.","method":"Anoikis-resistant cell model, mouse tail vein metastasis model, protein lactylation assay, mitochondrial morphology analysis, metabolic profiling","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel PTM (lactylation) on MIC60 identified with functional metabolic readouts; single lab, mechanistic follow-up limited in abstract","pmids":["40812308"],"is_preprint":false},{"year":2023,"finding":"Haploinsufficiency of Mic60 causes progressive neurological abnormalities with mitochondrial structural damage and neuronal loss in mice. Mic60 haploinsufficiency reduces mitochondrial membrane potential, cellular ATP production, increases ROS, and alters OXPHOS complexes in neurons in an age-dependent manner. Systemic N-acetylcysteine largely reverses mitochondrial dysfunction in haplo-insufficient Mic60 mice.","method":"Mic60 heterozygous mouse model, electron microscopy, mitochondrial membrane potential assay, ATP measurement, ROS assay, glucose brain imaging, Western blotting","journal":"Brain pathology (Zurich, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mouse haploinsufficiency model with multiple defined mitochondrial functional readouts; single lab","pmids":["36974636"],"is_preprint":false},{"year":2024,"finding":"L. monocytogenes virulence factor LLO directly interacts with Mic60 (via Phe251 of LLO) to trigger transient mitochondrial fission, enhancing bacterial pathogenicity. Mic60 affects the formation of F-actin tails recruited by L. monocytogenes. L. monocytogenes infection affects Mic60 expression, leading to changes in mitochondrial morphology, membrane potential, and ROS production.","method":"Co-immunoprecipitation, site-directed mutagenesis (Phe251), F-actin tail imaging, mitochondrial morphology assay, bacterial infection model","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and mutagenesis identifying interaction site between LLO and Mic60; single lab","pmids":["39431455"],"is_preprint":false},{"year":2023,"finding":"Carnosic acid prevents 6-OHDA-induced cytochrome c release by regulating Mic60 phosphorylation: PINK1 phosphorylates Mic60 on threonine residues (interaction decreased by 6-OHDA), while PKA phosphorylates Mic60 on serine residues. PINK1 siRNA and PKA activator (forskolin) reversed the Mic60 phosphorylation interactions. Mic60 and PINK1 siRNAs blocked carnosic acid's protective effect on cytochrome c release, establishing the PINK1-Mic60 axis in neuroprotection.","method":"Co-immunoprecipitation, siRNA knockdown, immunoprecipitation with phospho-specific antibodies, cytochrome c release assay","journal":"Food and chemical toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation site specificity (Thr vs Ser) determined by immunoprecipitation, functional rescue by siRNA; single lab, mechanistic detail limited in abstract","pmids":["36708866"],"is_preprint":false},{"year":2024,"finding":"Ancestral sequence reconstruction of the Mic60 Mitofilin domain identified four specific residues sufficient to explain the respiratory functional difference between yeast-lineage and animal-derived Mitofilin ancestors. Yeast-lineage Mitofilin ancestors as far back as the last opisthokont common ancestor rescue respiration in yeast, demonstrating that the C-terminal Mitofilin domain is required for cellular respiration.","method":"Ancestral sequence reconstruction, yeast complementation/rescue assay, comparative mutagenesis","journal":"Protein science","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — functional rescue in yeast with reconstructed ancestors and site-specific mutagenesis; single lab","pmids":["40545685"],"is_preprint":false}],"current_model":"IMMT (Mic60/Mitofilin) is a core inner mitochondrial membrane protein and essential scaffold of the MICOS complex that organizes cristae junctions and mediates inner-outer membrane contacts via a Sam50-Mic19-Mic60 axis; it interacts with OPA1 to control cristae shape (OPA1 epistatic to Mic60), is regulated by the i-AAA protease Yme1L, undergoes PKA-dependent phosphorylation at Ser528 (negatively regulating PINK1-Parkin mitophagy), is phosphorylated by PINK1 on threonine residues to stabilize its oligomerization and crista junction formation, is targeted for K48-linked ubiquitination at Lys285 by the E3 ligase MARCH5 (antagonized by TRAP1), is subject to lactylation affecting cristae remodeling, interacts with mtDNA transcription factors TFAM and TFB2M to support mitochondrial transcription, and its genetic ablation in mice is lethal within 12 days due to MICOS disruption and loss of mitochondrial structural integrity."},"narrative":{"mechanistic_narrative":"IMMT (Mic60/mitofilin) is a coiled-coil inner mitochondrial membrane protein that resides at the mitochondrial periphery and intermembrane space and serves as the core scaffold of the MICOS complex organizing cristae junctions [PMID:8886976, PMID:26250910]. Mic60 nucleates MICOS assembly—its loss destabilizes other MICOS subunits and disassembles the complex—through a direct interaction with Mic19/CHCHD3 that mediates mutual stabilization [PMID:26250910]. By bridging to the outer membrane through a Sam50–Mic19–Mic60 axis, it integrates the SAM and MICOS complexes into the MIB supercomplex that establishes inner–outer membrane contact sites at cristae junctions, a configuration whose disruption (e.g., by OMA1-mediated Mic19 cleavage) collapses cristae junctions and lowers ATP production [PMID:31097788, PMID:28808085]. Mic60 cooperates with OPA1, which is epistatic to Mic60 in setting cristae width and junction diameter, to control cristae shape [PMID:27974214], and it links cristae architecture to mtDNA function by interacting with TFAM and TFB2M and shaping the mtDNA D-loop to support mitochondrial transcription [PMID:25612828]. Its abundance and activity are tuned by post-translational control: K48-linked ubiquitination at Lys285 by MARCH5 (antagonized by TRAP1 binding) and by MDM2 drives its degradation [PMID:37679468, PMID:37315416], while reciprocal phosphorylation governs cristae and mitophagy—PINK1 phosphorylates Mic60 on threonine residues to stabilize oligomerization and crista junction formation, whereas PKA phosphorylation at Ser528 negatively regulates PINK1–Parkin mitophagy [PMID:27153535, PMID:29456190, PMID:36708866]. Mic60 is essential in vivo: inducible Immt deletion in adult mice disrupts MICOS and is lethal within 12 days, and homozygous IMMT variants cause a mitochondrial developmental encephalopathy with optic neuropathy through defective cristae organization [PMID:38467404, PMID:34842280].","teleology":[{"year":1996,"claim":"Established the basic identity and topology of mitofilin, answering where this protein sits before any functional role was known.","evidence":"Subcellular fractionation, immunoelectron microscopy, and limited proteolysis localizing the coiled-coil protein to the inner membrane/intermembrane space periphery","pmids":["8886976"],"confidence":"High","gaps":["No molecular function assigned","No interaction partners identified","Cristae role not yet established"]},{"year":2015,"claim":"Defined Mic60 as the core MICOS scaffold and linked cristae architecture to mtDNA transcription, moving from a structural protein to an organizing hub.","evidence":"shRNA knockdown with reciprocal Co-IP (Mic19/CHCHD3), EM morphology, mtDNA transcription assays, and TFAM/TFB2M binding plus mtDNA-3C in cultured cells","pmids":["26250910","25612828"],"confidence":"High","gaps":["Mechanism connecting cristae scaffold to D-loop architecture not resolved","Yme1L regulation of Mic60 not mechanistically dissected","TFAM/POLRMT recruitment causality unclear"]},{"year":2016,"claim":"Placed Mic60 within the cristae-shaping hierarchy by showing OPA1 is epistatic, and connected it to mitochondrial dynamics and neuronal survival.","evidence":"Native-complex proteomics, reciprocal Co-IP, double-knockdown epistasis, electron tomography (OPA1 axis); plus respirometry and cell-death assays in dopaminergic neuronal models","pmids":["27974214","27001148"],"confidence":"High","gaps":["Biochemical basis of OPA1–MIC60 epistasis unresolved","Direct vs indirect control of fission/fusion not distinguished"]},{"year":2016,"claim":"Identified phosphoregulation of Mic60 as a brake on PINK1–Parkin mitophagy, the first PTM control point on this scaffold.","evidence":"Mass-spectrometric phosphosite mapping (Ser528), phospho-mimic/dead mutagenesis with Parkin recruitment rescue, and Co-IP for transient PINK1 interaction","pmids":["27153535"],"confidence":"High","gaps":["How Ser528 phosphorylation alters MIC60 structure unknown","PKA upstream signaling context not defined"]},{"year":2017,"claim":"Resolved the nanoscale distribution of Mic60/Mic19/Sam50 to cristae junctions, providing physical grounding for the membrane-bridging model.","evidence":"Genetically encoded EM tags (miniSOG, APEX2) with electron tomography","pmids":["28808085"],"confidence":"High","gaps":["Functional meaning of intra-crista enrichment unclear","Stoichiometry at junctions not quantified"]},{"year":2018,"claim":"Established a direct PINK1 kinase–MIC60 substrate relationship that stabilizes oligomerization and crista junctions, with in vivo and disease relevance.","evidence":"Drosophila genetics, biochemical phosphorylation reconstitution, oligomerization assay, EM of crista junctions, rescue of PINK1-null phenotypes, and human neuron studies plus PD patient variants","pmids":["29456190"],"confidence":"High","gaps":["Phosphorylated threonine residues not all mapped","How phosphorylation drives oligomerization mechanistically unresolved"]},{"year":2019,"claim":"Defined the Sam50–Mic19–Mic60 axis as the structural bridge integrating SAM and MICOS into the MIB supercomplex linking the two mitochondrial membranes.","evidence":"Reciprocal Co-IP/pulldown, knockdown, super-resolution and electron microscopy, OMA1-cleavage dissection, and ATP assays","pmids":["31097788"],"confidence":"High","gaps":["Direct Mic60–Sam50 contact vs Mic19-bridged contact not fully separated","Regulation of OMA1 cleavage in physiology unclear"]},{"year":2017,"claim":"Extended Mic60 function beyond cristae to mitochondrial transport, showing it controls Miro levels and mitochondrial motility in neurons.","evidence":"Drosophila loss-of-function genetics, Western blotting of Miro, motility assays, and neuromuscular junction imaging","pmids":["28904209"],"confidence":"Medium","gaps":["Mechanism by which MIC60 regulates Miro abundance unknown","Whether this is conserved in mammals not tested"]},{"year":2021,"claim":"Identified ubiquitin-dependent control of MIC60 stability, with TRAP1 protecting MIC60 to preserve mitochondrial integrity under acidosis.","evidence":"Co-IP for TRAP1–MIC60, knockdown/overexpression with membrane potential and ATP readouts in cardiac injury models","pmids":["34907169"],"confidence":"Medium","gaps":["E3 ligase identity not defined in this study","Direct vs indirect protection by TRAP1 unclear"]},{"year":2023,"claim":"Mapped MARCH5 as a site-specific E3 ligase ubiquitinating MIC60 at Lys285, with TRAP1 acting as a competitive antagonist controlling MIC60 turnover.","evidence":"Co-IP, ubiquitination assays, site-directed mutagenesis, mass spectrometry, and knockdown under diabetic conditions","pmids":["37679468"],"confidence":"High","gaps":["Trigger linking metabolic stress to MARCH5 activation unclear","Relationship of MARCH5 pathway to MDM2 pathway not reconciled"]},{"year":2023,"claim":"Identified MDM2 as a second E3 ligase degrading MIC60, linking its loss to impaired mitophagy and microglial inflammation.","evidence":"In vivo mouse and in vitro ZnO-NP models, siRNA knockdown, ubiquitination and mitophagy assays","pmids":["37315416"],"confidence":"Medium","gaps":["MDM2 ubiquitination site on MIC60 not mapped","Overlap/competition with MARCH5 unresolved"]},{"year":2023,"claim":"Demonstrated organismal dependence on Mic60 dosage, showing haploinsufficiency drives age-dependent neurodegeneration through redox-sensitive mitochondrial dysfunction.","evidence":"Mic60 heterozygous mouse model with EM, membrane potential, ATP, ROS, and OXPHOS assays plus N-acetylcysteine rescue","pmids":["36974636"],"confidence":"Medium","gaps":["Causal step from cristae defect to neuronal loss not isolated","Why effects are age-dependent unexplained"]},{"year":2024,"claim":"Proved Mic60 is essential for adult mitochondrial integrity, establishing that acute MICOS loss is rapidly lethal.","evidence":"Tamoxifen-inducible conditional knockout mouse with EM, Western blotting, and pathology","pmids":["38467404"],"confidence":"High","gaps":["Tissue-specific contributions to lethality not parsed","Molecular cause of death sequence unresolved"]},{"year":2024,"claim":"Showed MIC60 is hijacked by pathogens, with Listeria LLO binding it to trigger fission and promote infection.","evidence":"Co-IP, LLO Phe251 mutagenesis, F-actin tail and mitochondrial morphology imaging in infection models","pmids":["39431455"],"confidence":"Medium","gaps":["How LLO binding triggers fission mechanistically unclear","Single Co-IP-based interaction model"]},{"year":2025,"claim":"Identified lactylation as a metabolic PTM on Mic60 that remodels cristae and drives therapy resistance, linking cristae architecture to cancer metabolism.","evidence":"Anoikis-resistant and metastasis models, protein lactylation assay, cristae morphology and metabolic profiling, with DAPK2 modulation","pmids":["40812308"],"confidence":"Medium","gaps":["Lactylation sites on Mic60 not mapped in abstract","Mechanism linking DAPK2 to Mic60 lactylation unclear"]},{"year":2025,"claim":"Used ancestral reconstruction to pinpoint the C-terminal Mitofilin domain as the determinant of respiratory function across eukaryotic lineages.","evidence":"Ancestral sequence reconstruction with yeast complementation and comparative mutagenesis","pmids":["40545685"],"confidence":"Medium","gaps":["Molecular activity of the four key residues not defined","Link to specific MICOS or respiratory partner unresolved"]},{"year":null,"claim":"How the multiple competing post-translational modifications (MARCH5/MDM2 ubiquitination, PINK1/PKA phosphorylation, lactylation) are integrated to set MIC60 abundance and cristae state in a given physiological context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling the PTM control points","Structural basis of MIC60 scaffolding at atomic resolution lacking","Mammalian conservation of the motility/Miro role untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,6]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,12]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,2,6,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,4,11]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5]}],"complexes":["MICOS","MIB supercomplex","SAM complex (via Sam50-Mic19-Mic60 axis)"],"partners":["MIC19/CHCHD3","SAMM50","OPA1","PINK1","TRAP1","MARCH5","TFAM","TFB2M"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16891","full_name":"MICOS complex subunit MIC60","aliases":["Cell proliferation-inducing gene 4/52 protein","Mitochondrial inner membrane protein","Mitofilin","p87/89"],"length_aa":758,"mass_kda":83.7,"function":"Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane (PubMed:22114354, PubMed:25781180, PubMed:32567732, PubMed:33130824). Plays an important role in the maintenance of the MICOS complex stability and the mitochondrial cristae morphology (PubMed:22114354, PubMed:25781180, PubMed:32567732, PubMed:33130824)","subcellular_location":"Mitochondrion inner membrane; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q16891/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IMMT","classification":"Not Classified","n_dependent_lines":137,"n_total_lines":1208,"dependency_fraction":0.11341059602649006},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DNAJC11","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IMMT","total_profiled":1310},"omim":[{"mim_id":"620399","title":"AARF DOMAIN-CONTAINING KINASE 1; ADCK1","url":"https://www.omim.org/entry/620399"},{"mim_id":"616658","title":"MITOCHONDRIAL CONTACT 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cells.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27641669","citation_count":8,"is_preprint":false},{"pmid":"21511719","id":"PMC_21511719","title":"Tomato LeTHIC is an Fe-requiring HMP-P synthase involved in thiamine synthesis and regulated by multiple factors.","date":"2011","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21511719","citation_count":8,"is_preprint":false},{"pmid":"39431455","id":"PMC_39431455","title":"The MICOS Complex Subunit Mic60 is Hijacked by Intracellular Bacteria to Manipulate Mitochondrial Dynamics and Promote Bacterial Pathogenicity.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39431455","citation_count":7,"is_preprint":false},{"pmid":"3554466","id":"PMC_3554466","title":"HMP-shunt and cholesterol metabolism in experimental models involving normal and preneoplastic liver 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elegans.","date":"2023","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36867663","citation_count":6,"is_preprint":false},{"pmid":"39236238","id":"PMC_39236238","title":"Single-molecule force spectroscopy reveals intra- and intermolecular interactions of Caenorhabditis elegans HMP-1 during mechanotransduction.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39236238","citation_count":6,"is_preprint":false},{"pmid":"34440185","id":"PMC_34440185","title":"HMP-S7 Is a Novel Anti-Leukemic Peptide Discovered from Human Milk.","date":"2021","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/34440185","citation_count":6,"is_preprint":false},{"pmid":"19152070","id":"PMC_19152070","title":"Expression of HMP/AN2, a melanoma associated antigen, in murine cerebral gliomas: potential for radioimmunotargeting.","date":"2009","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/19152070","citation_count":6,"is_preprint":false},{"pmid":"21752086","id":"PMC_21752086","title":"Nitrosative stress causes amino acid auxotrophy in hmp mutant Salmonella Typhimurium.","date":"2011","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21752086","citation_count":6,"is_preprint":false},{"pmid":"39367564","id":"PMC_39367564","title":"Whole cell affinity for 4-amino-5-hydroxymethyl-2-methylpyrimidine (HMP) in the marine bacterium Candidatus Pelagibacter st. HTCC7211 explains marine dissolved HMP concentrations.","date":"2024","source":"Environmental microbiology reports","url":"https://pubmed.ncbi.nlm.nih.gov/39367564","citation_count":5,"is_preprint":false},{"pmid":"38090711","id":"PMC_38090711","title":"Characterization of the enzyme kinetics of EMP and HMP pathway in Corynebacterium glutamicum: reference for modeling metabolic networks.","date":"2023","source":"Frontiers in bioengineering and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/38090711","citation_count":5,"is_preprint":false},{"pmid":"39209235","id":"PMC_39209235","title":"Electroacupuncture pretreatment maintains mitochondrial quality control via HO-1/MIC60 signaling pathway to alleviate endotoxin-induced acute lung injury.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39209235","citation_count":4,"is_preprint":false},{"pmid":"3287306","id":"PMC_3287306","title":"Comparative effects of insulin and refeeding on DNA synthesis, HMP shunt and cholesterogenesis in diabetic and fasted rats.","date":"1988","source":"Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/3287306","citation_count":4,"is_preprint":false},{"pmid":"7875715","id":"PMC_7875715","title":"Inhibition of two HMP shunt pathway enzymes by fatty acids and their CoA esters in developing human brain: role of fatty acid binding protein.","date":"1994","source":"Indian journal of biochemistry & biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/7875715","citation_count":4,"is_preprint":false},{"pmid":"11071267","id":"PMC_11071267","title":"Improving the performance of an acid-labile 4-hydroxymethyl phenoxyacetic acid (HMP) linker on resin and SynPhase grafted solid-supports.","date":"2000","source":"Journal of peptide science : an official publication of the European Peptide Society","url":"https://pubmed.ncbi.nlm.nih.gov/11071267","citation_count":4,"is_preprint":false},{"pmid":"36708866","id":"PMC_36708866","title":"Carnosic acid attenuated cytochrome c release through the mitochondrial structural protein Mic60 by PINK1 in SH-SY5Y cells.","date":"2023","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/36708866","citation_count":3,"is_preprint":false},{"pmid":"28591988","id":"PMC_28591988","title":"[Correlation between Mic60 haploid insufficiency and cardiac aging in mouse].","date":"2017","source":"Zhonghua bing li xue za zhi = Chinese journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/28591988","citation_count":3,"is_preprint":false},{"pmid":"23824318","id":"PMC_23824318","title":"The influence of CsgD on the expression of genes of folate metabolism and hmp in Escherichia coli K-12.","date":"2013","source":"Archives of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23824318","citation_count":3,"is_preprint":false},{"pmid":"26919528","id":"PMC_26919528","title":"Purification, crystallization and initial crystallographic analysis of the α-catenin homologue HMP-1 from Caenorhabditis elegans.","date":"2016","source":"Acta crystallographica. Section F, Structural biology communications","url":"https://pubmed.ncbi.nlm.nih.gov/26919528","citation_count":3,"is_preprint":false},{"pmid":"40545685","id":"PMC_40545685","title":"Ancestral sequence reconstruction of the Mic60 Mitofilin domain reveals residues supporting respiration in yeast.","date":"2025","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/40545685","citation_count":3,"is_preprint":false},{"pmid":"25805905","id":"PMC_25805905","title":"Molecular, Physiological and Phenotypic Characterization of Paracoccus denitrificans ATCC 19367 Mutant Strain P-87 Producing Improved Coenzyme Q10.","date":"2014","source":"Indian journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/25805905","citation_count":3,"is_preprint":false},{"pmid":"33034117","id":"PMC_33034117","title":"Functional characterization of the HMP-P synthase of Legionella pneumophila (Lpg1565).","date":"2020","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33034117","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46039,"output_tokens":6047,"usd":0.114411,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14907,"output_tokens":4902,"usd":0.098543,"stage2_stop_reason":"end_turn"},"total_usd":0.212954,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Mitofilin (IMMT/HMP) is a mitochondrial inner membrane protein that resides predominantly in the intermembrane space, contains predicted coiled-coil domains, is resistant to detergent extraction, co-purifies with mitochondria, and is not co-localized with Golgi or ER. Limited proteolysis and immuno-electron microscopy confirmed its intermembrane space localization at the mitochondrial periphery.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, immunoelectron microscopy, limited proteolysis, Western blotting\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, IEM, proteolysis, co-localization studies) in a single focused characterization paper; foundational localization and domain study\",\n      \"pmids\": [\"8886976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mic60/Mitofilin is a core scaffold for MICOS complex assembly: knockdown of Mic60 causes instability of other MICOS components and disassembly of the complex. Mic60 directly interacts with Mic19/CHCHD3, and this interaction is required for their mutual stabilization. Disrupted MICOS assembly causes giant mitochondria formation due to dysregulated fission/fusion, and mtDNA nucleoids become clustered and transcription is attenuated. The mitochondrial i-AAA protease Yme1L regulates Mic60 homeostasis.\",\n      \"method\": \"shRNA knockdown, co-immunoprecipitation, Western blotting, immunofluorescence, electron microscopy, mtDNA transcription assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, KD with multiple defined phenotypic readouts (MICOS disassembly, mitochondrial morphology, mtDNA transcription), and protease identification in single focused study\",\n      \"pmids\": [\"26250910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MIC60 physically interacts with OPA1, and together they control cristae junction number and stability. OPA1 is epistatic to MIC60 in cristae shape regulation: OPA1 defines cristae width and junction diameter independently of MIC60, while both are components of high-molecular-weight complexes disrupted during cristae remodeling. MIC60 is a core MICOS protein required for normal cristae junction formation.\",\n      \"method\": \"Proteomics of native complexes, co-immunoprecipitation, genetic epistasis (double KD), electron tomography, biochemistry\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, epistasis genetics, electron tomography with multiple orthogonal methods in single study\",\n      \"pmids\": [\"27974214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PKA phosphorylates MIC60 at Ser528. MIC60 transiently interacts with PINK1. MIC60 downregulation reduces PINK1 protein levels and causes mislocalization of Parkin. Phosphorylation-mimic MIC60 (Ser528Asp) fails to restore Parkin recruitment in MIC60-knockdown cells, while phosphorylation-deficient MIC60 (Ser528Ala) facilitates mitochondrial Parkin localization. Thus PKA-mediated phosphorylation of MIC60 negatively regulates the PINK1-Parkin mitophagy pathway.\",\n      \"method\": \"Mutational analysis, mass spectrometry, co-immunoprecipitation, shRNA knockdown, fluorescence microscopy\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometric identification of phosphosite, mutagenesis of phosphosite with functional rescue, Co-IP for PINK1 interaction; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"27153535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PINK1 phosphorylates the inner mitochondrial membrane protein MIC60/mitofilin in Drosophila and human neurons. PINK1-dependent phosphorylation stabilizes MIC60 oligomerization and promotes crista junction formation. Expression of MIC60 rescues crista structure, ATP levels, behavioral defects, and dopaminergic neurodegeneration in PINK1-null Drosophila. MIC60 coding variants in the mitochondrial targeting sequence found in PD patients impair crista junction formation in Drosophila.\",\n      \"method\": \"In vivo Drosophila genetics, biochemical reconstitution of phosphorylation, MIC60 oligomerization assay, electron microscopy of crista junctions, rescue experiments, human neuron studies\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct kinase-substrate relationship with in vivo rescue, oligomerization assay, electron microscopy, cross-species validation (Drosophila and human neurons)\",\n      \"pmids\": [\"29456190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mic60 interacts with mitochondrial transcription factors TFAM and TFB2M. Mic60 knockdown compromises mitochondrial transcription and OXPHOS activities, decreases TFAM binding and POLRMT recruitment to mtDNA promoters. Mic60 interacts with mtDNA and is involved in the architecture of the mtDNA D-loop region, as shown by mtDNA immunoprecipitation and 3C assays.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, ChIP on mtDNA, mIP-3C assay, OXPHOS activity measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with transcription factors, KD with functional readouts, novel mtDNA-3C assay; single lab\",\n      \"pmids\": [\"25612828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mic19 directly interacts with both Sam50 (outer membrane SAM complex) and Mic60 (MICOS complex) to form a Sam50-Mic19-Mic60 axis that integrates SAM and MICOS into the MIB (mitochondrial intermembrane space bridging) supercomplex, mediating outer- and inner-membrane contact. OMA1-mediated cleavage of Mic19 disrupts this axis, causing MIB disassembly, loss of cristae junctions, and reduced ATP production. Sam50 acts as an anchoring point guiding cristae junction formation at the outer membrane.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, knockdown, super-resolution microscopy, electron microscopy, ATP production assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing ternary complex, OMA1 cleavage mechanistic dissection, KD with defined phenotypic readouts across multiple methods in single focused study\",\n      \"pmids\": [\"31097788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mic19, Mic60, and Sam50 localize specifically to crista junctions in a network pattern along the mitochondrial periphery, with enrichment also inside cristae, as determined by miniSOG and APEX2 genetic tags and electron tomography at nanoscale resolution. Sam50 is not uniformly distributed in the outer mitochondrial membrane and incompletely overlaps with Mic19/Mic60 at crista junctions.\",\n      \"method\": \"Genetically encoded electron microscopy tags (miniSOG, APEX2), electron tomography, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — nanoscale electron tomography with genetic tags; novel high-resolution localization with functional context in single lab study\",\n      \"pmids\": [\"28808085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Drosophila MIC60 performs dual functions: (1) maintenance of crista membrane structure (canonical role) and (2) regulation of mitochondrial motility by influencing protein levels of the outer mitochondrial membrane protein Miro that anchors mitochondria to microtubule motors. Loss of MIC60 causes loss of Miro and mitochondrial arrest, and disrupts synaptic structure and function at neuromuscular junctions.\",\n      \"method\": \"Drosophila genetic mutant analysis, Western blotting, mitochondrial motility assays, neuromuscular junction imaging, electron microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function genetics with defined phenotypic readouts (motility, Miro levels, NMJ structure); single lab, Drosophila model\",\n      \"pmids\": [\"28904209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MARCH5 acts as an E3 ubiquitin ligase that specifically targets MIC60, mediating K48-linked ubiquitination at Lys285 to promote its degradation under high glucose/palmitate (diabetic) conditions. TRAP1 inhibits MARCH5-mediated ubiquitination by competitively binding to MIC60. Mutation of the MIC60 ubiquitination site (Lys285) or the MIC60-interacting motifs in MARCH5 abrogates MARCH5-mediated MIC60 ubiquitination and degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, mass spectrometry, shRNA knockdown, overexpression\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-specific ubiquitination mapped by mutagenesis and mass spectrometry, competitive binding assay, functional rescue; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37679468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRAP1 mitigates extracellular acidosis-induced mitochondrial impairment and cardiac injury by directly interacting with MIC60 to decrease its ubiquitin-dependent degradation. Overexpression of MIC60 in acidosis maintains cell viability, increases ATP production, mitochondrial membrane potential, and mitigates disruption of mitochondrial structure.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, shRNA knockdown, mitochondrial membrane potential assay, ATP measurement\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for TRAP1-MIC60 interaction, KD/OE with functional readouts; single lab\",\n      \"pmids\": [\"34907169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MDM2 acts as an E3 ubiquitin ligase that increases MIC60 ubiquitination, causing its degradation, which impairs mitophagy and induces autophagosome overaccumulation and microglial inflammation. MDM2 silencing significantly attenuates mitochondrial damage caused by ZnO-NPs by preventing MIC60 ubiquitination and degradation.\",\n      \"method\": \"In vivo mouse model, in vitro ZnO-NP exposure, siRNA knockdown, ubiquitination assay, mitophagy assay, immunofluorescence\",\n      \"journal\": \"Journal of hazardous materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identification of MDM2 as E3 ligase with functional rescue via silencing; single lab, in vivo and in vitro\",\n      \"pmids\": [\"37315416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tamoxifen-inducible deletion of Immt in adult mice disrupts the MICOS complex, increases mitochondrial size, alters cristae morphology, and is lethal within 12 days, demonstrating that MIC60 is essential for MICOS integrity in vivo. Pathological consequences include defective intestinal muscle function (paralytic ileus) and bone marrow hypocellularity.\",\n      \"method\": \"Conditional knockout mouse model (ROSA-CreERT2), electron microscopy, Western blotting, pathological analysis\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous conditional KO mouse model with defined molecular (MICOS disruption) and organismal phenotypic consequences; in vivo genetic ablation\",\n      \"pmids\": [\"38467404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MIC60 was identified as the direct binding target of the small molecule miclxin using drug-immobilized affinity beads. MIC60 dysfunction caused by miclxin induces a mitochondrial stress response in a mutant β-catenin-dependent manner, leading to Bcl-2 downregulation, loss of mitochondrial membrane potential, and apoptosis-inducing factor-dependent apoptosis.\",\n      \"method\": \"Affinity bead pulldown (drug-immobilized beads), Western blotting, flow cytometry, cell death assays\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct drug-affinity pulldown identifying MIC60 as target, functional consequences of MIC60 inhibition established; single lab\",\n      \"pmids\": [\"32584541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mic60/mitofilin overexpression in dopaminergic neuronal cells attenuates dopamine- and rotenone-induced cell death, increases mitochondrial respiration and spare respiratory capacity, suppresses mitochondrial fission, and increases mitochondrial length in neurites. Mic60 knockdown potentiates dopamine-induced cell death and suppresses respiration, demonstrating that Mic60 controls both mitochondrial membrane function and fission/fusion dynamics in neurons.\",\n      \"method\": \"shRNA knockdown, overexpression, Seahorse respirometry, mitochondrial imaging, cell death assays in differentiated SH-SY5Y and PC12 cells and primary rat cortical neurons\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with multiple functional readouts (respiration, morphology, cell death); single lab, multiple cell models\",\n      \"pmids\": [\"27001148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Alphaproteobacterial Mic60 (ortholog of eukaryotic IMMT/Mic60) physically interacts with BamA, the homolog of Sam50, recapitulating the conserved Mic60-Sam50 interaction from bacteria to mitochondria. Disruption of Mic60 and adjacent gene Orf52 in Rhodobacter sphaeroides and Rhodopseudomonas palustris causes photoheterotrophic growth defects and enlarged intracytoplasmic membranes (ICMs), supporting a role in ICM/crista organization.\",\n      \"method\": \"Genetic disruption, overexpression, physical interaction assay, electron microscopy, photoheterotrophic growth assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct physical interaction demonstrated for BamA-Mic60 in bacteria, genetic loss-of-function with ICM phenotype; single lab, bacterial ortholog\",\n      \"pmids\": [\"36921606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Homozygous pathogenic variants (c.895A>G, p.Lys299Glu) in IMMT cause mitochondrial developmental encephalopathy with optic neuropathy in humans. Functional studies showed that loss of IMMT function causes alterations in mitochondrial cristae morphology, confirming the essential role of IMMT/mitofilin in cristae organization in vivo.\",\n      \"method\": \"Clinical genetics, Sanger sequencing, electron microscopy of patient mitochondria, co-segregation analysis\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human disease-causing variant with electron microscopy confirmation of cristae defect; single family/case but direct functional validation\",\n      \"pmids\": [\"34842280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Lactylation of Mic60 protein is a critical post-translational modification that affects mitochondrial cristae remodeling and activates mitochondrial metabolism. Dysfunction of DAPK2 kinase alters Mic60 protein in mitochondrial cristae, increasing cristae abundance and compactness and activating mitochondrial metabolism, contributing to EGFR-TKI resistance and cancer metastasis.\",\n      \"method\": \"Anoikis-resistant cell model, mouse tail vein metastasis model, protein lactylation assay, mitochondrial morphology analysis, metabolic profiling\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel PTM (lactylation) on MIC60 identified with functional metabolic readouts; single lab, mechanistic follow-up limited in abstract\",\n      \"pmids\": [\"40812308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Haploinsufficiency of Mic60 causes progressive neurological abnormalities with mitochondrial structural damage and neuronal loss in mice. Mic60 haploinsufficiency reduces mitochondrial membrane potential, cellular ATP production, increases ROS, and alters OXPHOS complexes in neurons in an age-dependent manner. Systemic N-acetylcysteine largely reverses mitochondrial dysfunction in haplo-insufficient Mic60 mice.\",\n      \"method\": \"Mic60 heterozygous mouse model, electron microscopy, mitochondrial membrane potential assay, ATP measurement, ROS assay, glucose brain imaging, Western blotting\",\n      \"journal\": \"Brain pathology (Zurich, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mouse haploinsufficiency model with multiple defined mitochondrial functional readouts; single lab\",\n      \"pmids\": [\"36974636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"L. monocytogenes virulence factor LLO directly interacts with Mic60 (via Phe251 of LLO) to trigger transient mitochondrial fission, enhancing bacterial pathogenicity. Mic60 affects the formation of F-actin tails recruited by L. monocytogenes. L. monocytogenes infection affects Mic60 expression, leading to changes in mitochondrial morphology, membrane potential, and ROS production.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (Phe251), F-actin tail imaging, mitochondrial morphology assay, bacterial infection model\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and mutagenesis identifying interaction site between LLO and Mic60; single lab\",\n      \"pmids\": [\"39431455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Carnosic acid prevents 6-OHDA-induced cytochrome c release by regulating Mic60 phosphorylation: PINK1 phosphorylates Mic60 on threonine residues (interaction decreased by 6-OHDA), while PKA phosphorylates Mic60 on serine residues. PINK1 siRNA and PKA activator (forskolin) reversed the Mic60 phosphorylation interactions. Mic60 and PINK1 siRNAs blocked carnosic acid's protective effect on cytochrome c release, establishing the PINK1-Mic60 axis in neuroprotection.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunoprecipitation with phospho-specific antibodies, cytochrome c release assay\",\n      \"journal\": \"Food and chemical toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation site specificity (Thr vs Ser) determined by immunoprecipitation, functional rescue by siRNA; single lab, mechanistic detail limited in abstract\",\n      \"pmids\": [\"36708866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ancestral sequence reconstruction of the Mic60 Mitofilin domain identified four specific residues sufficient to explain the respiratory functional difference between yeast-lineage and animal-derived Mitofilin ancestors. Yeast-lineage Mitofilin ancestors as far back as the last opisthokont common ancestor rescue respiration in yeast, demonstrating that the C-terminal Mitofilin domain is required for cellular respiration.\",\n      \"method\": \"Ancestral sequence reconstruction, yeast complementation/rescue assay, comparative mutagenesis\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional rescue in yeast with reconstructed ancestors and site-specific mutagenesis; single lab\",\n      \"pmids\": [\"40545685\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IMMT (Mic60/Mitofilin) is a core inner mitochondrial membrane protein and essential scaffold of the MICOS complex that organizes cristae junctions and mediates inner-outer membrane contacts via a Sam50-Mic19-Mic60 axis; it interacts with OPA1 to control cristae shape (OPA1 epistatic to Mic60), is regulated by the i-AAA protease Yme1L, undergoes PKA-dependent phosphorylation at Ser528 (negatively regulating PINK1-Parkin mitophagy), is phosphorylated by PINK1 on threonine residues to stabilize its oligomerization and crista junction formation, is targeted for K48-linked ubiquitination at Lys285 by the E3 ligase MARCH5 (antagonized by TRAP1), is subject to lactylation affecting cristae remodeling, interacts with mtDNA transcription factors TFAM and TFB2M to support mitochondrial transcription, and its genetic ablation in mice is lethal within 12 days due to MICOS disruption and loss of mitochondrial structural integrity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IMMT (Mic60/mitofilin) is a coiled-coil inner mitochondrial membrane protein that resides at the mitochondrial periphery and intermembrane space and serves as the core scaffold of the MICOS complex organizing cristae junctions [#0, #1]. Mic60 nucleates MICOS assembly—its loss destabilizes other MICOS subunits and disassembles the complex—through a direct interaction with Mic19/CHCHD3 that mediates mutual stabilization [#1]. By bridging to the outer membrane through a Sam50–Mic19–Mic60 axis, it integrates the SAM and MICOS complexes into the MIB supercomplex that establishes inner–outer membrane contact sites at cristae junctions, a configuration whose disruption (e.g., by OMA1-mediated Mic19 cleavage) collapses cristae junctions and lowers ATP production [#6, #7]. Mic60 cooperates with OPA1, which is epistatic to Mic60 in setting cristae width and junction diameter, to control cristae shape [#2], and it links cristae architecture to mtDNA function by interacting with TFAM and TFB2M and shaping the mtDNA D-loop to support mitochondrial transcription [#5]. Its abundance and activity are tuned by post-translational control: K48-linked ubiquitination at Lys285 by MARCH5 (antagonized by TRAP1 binding) and by MDM2 drives its degradation [#9, #11], while reciprocal phosphorylation governs cristae and mitophagy—PINK1 phosphorylates Mic60 on threonine residues to stabilize oligomerization and crista junction formation, whereas PKA phosphorylation at Ser528 negatively regulates PINK1–Parkin mitophagy [#3, #4, #20]. Mic60 is essential in vivo: inducible Immt deletion in adult mice disrupts MICOS and is lethal within 12 days, and homozygous IMMT variants cause a mitochondrial developmental encephalopathy with optic neuropathy through defective cristae organization [#12, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the basic identity and topology of mitofilin, answering where this protein sits before any functional role was known.\",\n      \"evidence\": \"Subcellular fractionation, immunoelectron microscopy, and limited proteolysis localizing the coiled-coil protein to the inner membrane/intermembrane space periphery\",\n      \"pmids\": [\"8886976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No molecular function assigned\", \"No interaction partners identified\", \"Cristae role not yet established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined Mic60 as the core MICOS scaffold and linked cristae architecture to mtDNA transcription, moving from a structural protein to an organizing hub.\",\n      \"evidence\": \"shRNA knockdown with reciprocal Co-IP (Mic19/CHCHD3), EM morphology, mtDNA transcription assays, and TFAM/TFB2M binding plus mtDNA-3C in cultured cells\",\n      \"pmids\": [\"26250910\", \"25612828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting cristae scaffold to D-loop architecture not resolved\", \"Yme1L regulation of Mic60 not mechanistically dissected\", \"TFAM/POLRMT recruitment causality unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed Mic60 within the cristae-shaping hierarchy by showing OPA1 is epistatic, and connected it to mitochondrial dynamics and neuronal survival.\",\n      \"evidence\": \"Native-complex proteomics, reciprocal Co-IP, double-knockdown epistasis, electron tomography (OPA1 axis); plus respirometry and cell-death assays in dopaminergic neuronal models\",\n      \"pmids\": [\"27974214\", \"27001148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical basis of OPA1–MIC60 epistasis unresolved\", \"Direct vs indirect control of fission/fusion not distinguished\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified phosphoregulation of Mic60 as a brake on PINK1–Parkin mitophagy, the first PTM control point on this scaffold.\",\n      \"evidence\": \"Mass-spectrometric phosphosite mapping (Ser528), phospho-mimic/dead mutagenesis with Parkin recruitment rescue, and Co-IP for transient PINK1 interaction\",\n      \"pmids\": [\"27153535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ser528 phosphorylation alters MIC60 structure unknown\", \"PKA upstream signaling context not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the nanoscale distribution of Mic60/Mic19/Sam50 to cristae junctions, providing physical grounding for the membrane-bridging model.\",\n      \"evidence\": \"Genetically encoded EM tags (miniSOG, APEX2) with electron tomography\",\n      \"pmids\": [\"28808085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional meaning of intra-crista enrichment unclear\", \"Stoichiometry at junctions not quantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established a direct PINK1 kinase–MIC60 substrate relationship that stabilizes oligomerization and crista junctions, with in vivo and disease relevance.\",\n      \"evidence\": \"Drosophila genetics, biochemical phosphorylation reconstitution, oligomerization assay, EM of crista junctions, rescue of PINK1-null phenotypes, and human neuron studies plus PD patient variants\",\n      \"pmids\": [\"29456190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylated threonine residues not all mapped\", \"How phosphorylation drives oligomerization mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the Sam50–Mic19–Mic60 axis as the structural bridge integrating SAM and MICOS into the MIB supercomplex linking the two mitochondrial membranes.\",\n      \"evidence\": \"Reciprocal Co-IP/pulldown, knockdown, super-resolution and electron microscopy, OMA1-cleavage dissection, and ATP assays\",\n      \"pmids\": [\"31097788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Mic60–Sam50 contact vs Mic19-bridged contact not fully separated\", \"Regulation of OMA1 cleavage in physiology unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended Mic60 function beyond cristae to mitochondrial transport, showing it controls Miro levels and mitochondrial motility in neurons.\",\n      \"evidence\": \"Drosophila loss-of-function genetics, Western blotting of Miro, motility assays, and neuromuscular junction imaging\",\n      \"pmids\": [\"28904209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which MIC60 regulates Miro abundance unknown\", \"Whether this is conserved in mammals not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified ubiquitin-dependent control of MIC60 stability, with TRAP1 protecting MIC60 to preserve mitochondrial integrity under acidosis.\",\n      \"evidence\": \"Co-IP for TRAP1–MIC60, knockdown/overexpression with membrane potential and ATP readouts in cardiac injury models\",\n      \"pmids\": [\"34907169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase identity not defined in this study\", \"Direct vs indirect protection by TRAP1 unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped MARCH5 as a site-specific E3 ligase ubiquitinating MIC60 at Lys285, with TRAP1 acting as a competitive antagonist controlling MIC60 turnover.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, site-directed mutagenesis, mass spectrometry, and knockdown under diabetic conditions\",\n      \"pmids\": [\"37679468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger linking metabolic stress to MARCH5 activation unclear\", \"Relationship of MARCH5 pathway to MDM2 pathway not reconciled\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified MDM2 as a second E3 ligase degrading MIC60, linking its loss to impaired mitophagy and microglial inflammation.\",\n      \"evidence\": \"In vivo mouse and in vitro ZnO-NP models, siRNA knockdown, ubiquitination and mitophagy assays\",\n      \"pmids\": [\"37315416\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MDM2 ubiquitination site on MIC60 not mapped\", \"Overlap/competition with MARCH5 unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated organismal dependence on Mic60 dosage, showing haploinsufficiency drives age-dependent neurodegeneration through redox-sensitive mitochondrial dysfunction.\",\n      \"evidence\": \"Mic60 heterozygous mouse model with EM, membrane potential, ATP, ROS, and OXPHOS assays plus N-acetylcysteine rescue\",\n      \"pmids\": [\"36974636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal step from cristae defect to neuronal loss not isolated\", \"Why effects are age-dependent unexplained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proved Mic60 is essential for adult mitochondrial integrity, establishing that acute MICOS loss is rapidly lethal.\",\n      \"evidence\": \"Tamoxifen-inducible conditional knockout mouse with EM, Western blotting, and pathology\",\n      \"pmids\": [\"38467404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions to lethality not parsed\", \"Molecular cause of death sequence unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed MIC60 is hijacked by pathogens, with Listeria LLO binding it to trigger fission and promote infection.\",\n      \"evidence\": \"Co-IP, LLO Phe251 mutagenesis, F-actin tail and mitochondrial morphology imaging in infection models\",\n      \"pmids\": [\"39431455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How LLO binding triggers fission mechanistically unclear\", \"Single Co-IP-based interaction model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified lactylation as a metabolic PTM on Mic60 that remodels cristae and drives therapy resistance, linking cristae architecture to cancer metabolism.\",\n      \"evidence\": \"Anoikis-resistant and metastasis models, protein lactylation assay, cristae morphology and metabolic profiling, with DAPK2 modulation\",\n      \"pmids\": [\"40812308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lactylation sites on Mic60 not mapped in abstract\", \"Mechanism linking DAPK2 to Mic60 lactylation unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Used ancestral reconstruction to pinpoint the C-terminal Mitofilin domain as the determinant of respiratory function across eukaryotic lineages.\",\n      \"evidence\": \"Ancestral sequence reconstruction with yeast complementation and comparative mutagenesis\",\n      \"pmids\": [\"40545685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular activity of the four key residues not defined\", \"Link to specific MICOS or respiratory partner unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple competing post-translational modifications (MARCH5/MDM2 ubiquitination, PINK1/PKA phosphorylation, lactylation) are integrated to set MIC60 abundance and cristae state in a given physiological context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling the PTM control points\", \"Structural basis of MIC60 scaffolding at atomic resolution lacking\", \"Mammalian conservation of the motility/Miro role untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 2, 6, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 4, 11]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"MICOS\", \"MIB supercomplex\", \"SAM complex (via Sam50-Mic19-Mic60 axis)\"],\n    \"partners\": [\"MIC19/CHCHD3\", \"SAMM50\", \"OPA1\", \"PINK1\", \"TRAP1\", \"MARCH5\", \"TFAM\", \"TFB2M\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}