{"gene":"RHOT1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2009,"finding":"Miro1 physically links mitochondria to KIF5 kinesin motor proteins, enabling microtubule-based transport. Ca2+ binding to Miro1's EF-hand domains (at micromolar levels) inhibits this linkage, halting mitochondrial movement. Mutation of EF-hand domains to prevent Ca2+ binding blocked glutamate/NMDA receptor-induced mitochondrial stopping but preserved basal motility.","method":"Dominant-negative EF-hand mutant expression, live-cell imaging, neuronal activity manipulation (glutamate/NMDA stimulation), Co-IP of Miro1 with KIF5","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (mutagenesis, live imaging, co-IP), replicated across conditions, foundational mechanistic study","pmids":["19249275"],"is_preprint":false},{"year":2008,"finding":"Miro1 recruits the adaptor protein Grif-1 (TRAK2) to mitochondria in a GTPase-dependent manner. This Miro1–Grif-1 complex promotes anterograde transport of mitochondria into neuronal processes. Mutation of Miro1's first GTPase domain impairs Grif-1 recruitment and alters mitochondrial distribution and morphology.","method":"Co-IP, overexpression/dominant-negative constructs, live neuronal imaging, subcellular fractionation","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, GTPase mutant analysis, live imaging; multiple orthogonal methods in single rigorous study","pmids":["19103291"],"is_preprint":false},{"year":2014,"finding":"Miro1 knockout in mice depletes mitochondria from corticospinal tract axons and causes progressive upper motor neuron disease and developmental defects in cranial motor nuclei. Miro1-deficient neurons show defective retrograde axonal mitochondrial transport but retain normal mitochondrial respiratory function and Ca2+-mediated inhibition of movement.","method":"Neuron-specific Miro1 knockout mice, immunofluorescence, neurological behavioral analysis, axonal transport assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse model with defined neurological phenotype, multiple readouts including transport and respiratory function","pmids":["25136135"],"is_preprint":false},{"year":2014,"finding":"Parkin ubiquitylates Miro1 at conserved lysine residues (K153, K230, K235, K330, K572) in a PINK1 phosphorylation-dependent manner. PINK1 phosphorylation of Parkin at Ser65 is required for substrate (Miro1) ubiquitylation. Miro1 serves as a direct substrate of activated Parkin E3 ligase.","method":"In vitro E3 ligase reconstitution assay with recombinant full-length untagged Parkin and Miro1, mass spectrometry identification of ubiquitylation sites, mutagenesis of Parkin catalytic cysteine and disease variants","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant proteins, mass spectrometry site mapping, mutagenesis validation, multiple orthogonal assays","pmids":["24647965"],"is_preprint":false},{"year":2017,"finding":"Miro1 deletion in mouse embryonic fibroblasts restricts mitochondria to the perinuclear area, depleting peripheral ATP:ADP ratios, and thereby impairs actin dynamics, lamellipodia protrusion, focal adhesion assembly/stability, and cell migration (both collective and single-cell).","method":"Miro1-/- MEF cells, genetically encoded ATP:ADP biosensor (PercevalHR), live-cell imaging, focal adhesion immunofluorescence, migration assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells with defined phenotype, multiple orthogonal methods (biosensor, imaging, functional assays), causal link between positioning and energy gradients","pmids":["28615318"],"is_preprint":false},{"year":2013,"finding":"DISC1 forms a complex with TRAK1 (trafficking kinesin-binding protein 1) and Miro1 on mitochondria and specifically promotes anterograde axonal mitochondrial transport. A rare DISC1 variant (37W) impairs anterograde transport and redistributes mitochondrial DISC1.","method":"Co-IP (DISC1–TRAK1–Miro1 complex), live neuronal axon imaging, disease-variant functional analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP establishing complex membership, live imaging showing anterograde transport role; single lab","pmids":["24092329"],"is_preprint":false},{"year":2014,"finding":"Miro1 regulates intercellular mitochondrial transfer from mesenchymal stem cells (MSC) to epithelial cells. Miro1 overexpression in MSC enhances mitochondrial transfer and therapeutic rescue of epithelial injury; Miro1 knockdown reduces transfer efficacy.","method":"Miro1 overexpression/knockdown in MSC, fluorescent mitochondria tracking, mouse models of airway injury and allergic inflammation","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with direct mitochondrial transfer quantification, in vivo validation, single lab","pmids":["24431222"],"is_preprint":false},{"year":2014,"finding":"Miro-1 associates with the dynein motor complex on lymphocyte mitochondria, and Miro-1 silencing impairs mitochondrial redistribution to the MTOC during chemokine CXCL12-induced polarization, reducing myosin II activation and actin polymerization, thereby impairing lymphocyte adhesion and migration.","method":"Miro-1 siRNA knockdown, co-IP with dynein, live-cell imaging, flow adhesion assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying dynein interaction, KD with defined migratory phenotype, single lab","pmids":["24492963"],"is_preprint":false},{"year":2017,"finding":"ALS mutant SOD1 reduces endogenous Miro1 protein levels through PINK1/Parkin-dependent degradation (not via elevated cytosolic Ca2+), causing impaired anterograde axonal mitochondrial transport. Miro1 overexpression or PINK1 ablation rescues this transport deficit.","method":"ALS mutant SOD1 transfection in cortical and motor neurons, Miro1 protein level quantification, mitochondrial transport imaging, Parkin-dependence shown by co-expression experiments, Ca2+ measurements","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiments (Miro1 OE, PINK1 KO), negative result for Ca2+ mechanism, multiple neuron types; single lab","pmids":["28973175"],"is_preprint":false},{"year":2018,"finding":"Miro1 and Miro2 are identified as mitochondrial receptors for myosin XIX (Myo19). Miro1 binds directly to the C-terminal tail of Myo19, recruits it to mitochondria in vivo, and this recruitment is regulated by the GTPase state of Miro1's N-terminal Rho-GTPase domain. Myo19 protein stability depends on its association with Miro1/2.","method":"Proximity labeling, direct binding assays (pulldown), in vivo recruitment assays, Miro1/2 knockdown and overexpression, protein stability analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding demonstrated, proximity labeling, in vivo recruitment, GTPase-state dependence by mutagenesis; multiple orthogonal methods","pmids":["30111583"],"is_preprint":false},{"year":2018,"finding":"Miro1, through its EF-hand domain 1, senses cytosolic Ca2+ elevation and mediates a distinct mitochondrial shape transition (MiST) that is independent of classical fission or swelling. Ca2+-dependent disruption of the Miro1/KIF5B/tubulin complex is controlled by the EF1 domain. Miro1-dependent MiST is required for autophagy/mitophagy initiation.","method":"EF-hand mutant expression, live-cell Ca2+ manipulation, GPCR activation, morphometric analysis, Miro1 KO cells, autophagy/mitophagy assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — EF-hand mutagenesis, multiple cell types, Ca2+ manipulation with functional readout, mitophagy assays; multiple orthogonal methods","pmids":["29694881"],"is_preprint":false},{"year":2016,"finding":"Miro1 Ca2+-sensing (EF-hand) function is required for activity-dependent repositioning of mitochondria to presynaptic terminals during prolonged neuronal activity. This repositioning decreases presynaptic Ca2+ signals and neurotransmitter release, enabling homeostatic plasticity.","method":"Miro1 EF-hand mutant neurons, genetically encoded presynaptic Ca2+ indicator SyGCaMP5, live imaging, electrophysiology","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — EF-hand mutant analysis, genetically encoded biosensors, live imaging, functional synaptic readout; multiple methods","pmids":["28039205"],"is_preprint":false},{"year":2015,"finding":"Miro1 Ca2+-sensing EF-hand domains regulate activity-dependent mitochondrial confinement in astrocytic processes near synapses. Miro1-mediated mitochondrial positioning reciprocally regulates intracellular Ca2+ signaling levels in astrocytic processes.","method":"EF-hand mutant Miro1 expression, live-cell confocal microscopy in rat organotypic hippocampal slices, Ca2+ imaging","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — EF-hand mutagenesis in organotypic slices, live Ca2+ imaging, activity-driven mitochondrial positioning quantified; multiple methods","pmids":["26631479"],"is_preprint":false},{"year":2017,"finding":"Three splice variants of human Miro1 (var2, var3, var4) containing sequence insertions upstream of the transmembrane domain localize to peroxisomes, recognized by the cytosolic receptor Pex19. Peroxisomal Miro1 variants act as adaptors linking peroxisomes to TRAK2-containing microtubule transport complexes, promoting long-range peroxisome movement.","method":"Identification and characterization of splice variants, peroxisome localization by immunofluorescence, Pex19 interaction studies, MIRO1 knockdown/re-expression, live-cell peroxisome tracking","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — splice variant characterization, organelle localization, receptor interaction, rescue experiments; multiple orthogonal methods","pmids":["29222186"],"is_preprint":false},{"year":2018,"finding":"Miro1 localizes to peroxisomes (in addition to mitochondria) and regulates microtubule-dependent peroxisome motility. Miro1's transmembrane domain mediates interaction with the peroxisomal membrane chaperone Pex19. Miro1-mediated pulling forces contribute to peroxisome membrane elongation and proliferation.","method":"Microscopy, live-cell imaging, mathematical modelling, peroxisome-targeted Miro1 fusion protein, Miro1 knockdown","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments, functional Miro1 fusion construct, quantitative motility analysis; single lab","pmids":["29364559"],"is_preprint":false},{"year":2019,"finding":"In Parkinson's disease patient fibroblasts (>94%), Miro1 fails to be removed from depolarized mitochondria, blocking initiation of mitophagy. PINK1, Parkin, and LRRK2 are required molecular helpers for Miro1 removal from dysfunctional mitochondria. A small molecule that reduces Miro1 levels repairs this defect and rescues locomotor deficits and dopaminergic neurodegeneration in patient-derived neurons and fly PD models.","method":"Biochemical Miro1 depolarization assay in patient fibroblasts, iPSC-derived neurons, Drosophila PD models, small molecule screen","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient fibroblasts (broad cohort), iPSC neurons, in vivo fly rescue; multiple systems and methods","pmids":["31564441"],"is_preprint":false},{"year":2019,"finding":"RHOT1 mutations in PD patients (het c.815G>A; het c.1348C>T) reduce mitochondrial-ER contact sites (MERCs) and disrupt Ca2+ homeostasis in patient-derived fibroblasts, impairing energy metabolism and increasing mitophagy.","method":"Patient fibroblast live-cell imaging, immunocytochemistry for MERCs, Ca2+ homeostasis assays, mitophagy quantification","journal":"Antioxidants & redox signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cellular models, multiple functional readouts, live imaging; single lab","pmids":["31303019"],"is_preprint":false},{"year":2020,"finding":"Miro1 Ser156 phosphorylation is a PINK1-regulated modification affecting Miro1 steady-state protein levels and degradation during mitophagy. A phospho-null S156A mutation causes significant depletion of Miro1 protein, impairs further degradation upon mitophagy induction, leads to slightly elongated mitochondria, and reduces mitochondrial oxygen consumption with depletion of OXPHOS complexes III and V in human dopaminergic neurons.","method":"CRISPR/Cas9 gene-edited iPSC (homozygous S156A), differentiation to dopaminergic neurons, mitophagy induction (CCCP), immunoblotting, Seahorse respirometry, live-cell mitochondrial movement imaging","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene-edited human iPSC neurons, multiple functional readouts; single lab, single publication","pmids":["35455950"],"is_preprint":false},{"year":2020,"finding":"DISC1 promotes anterograde mitochondrial transport in a manner dependent on Miro1's GTP-bound (active) state at the first GTPase domain. The first GTPase domain of Miro1 determines the direction of mitochondrial transport.","method":"Miro1 GTPase domain mutants, live neuronal imaging, DISC1 co-expression experiments","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GTPase domain mutagenesis, live imaging of directional transport; single lab","pmids":["32637409"],"is_preprint":false},{"year":2020,"finding":"Miro1 interacts with Mitofusin (MFN) and inhibits MFN-mediated mitochondrial outer membrane fusion in response to elevated mitochondrial Ca2+ concentration. This inhibition requires Miro1's EF-hand domain 1. Lowering mitochondrial Ca2+ or knocking down Miro1/2 promotes network fusion.","method":"Co-IP, proximity labeling proteomics (BioID), EF-hand mutant expression, ectopic MFN expression, MCU inhibitor treatment, Miro1/2 knockdown","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and proximity labeling establishing interaction, EF-hand mutagenesis for Ca2+ dependence; single lab","pmids":["34431132"],"is_preprint":false},{"year":2020,"finding":"Miro1 deletion in Miro1-/- MEFs restricts subcellular H2O2 to the perinuclear area and prevents peripheral oxidation of cytosolic peroxiredoxin 2 (PRX2) after mitochondrial complex I inhibition. Local H2O2 levels correlate with focal adhesion size and abundance; Miro1-/- cells have smaller focal adhesions with reduced vinculin and p130Cas phosphorylation.","method":"Miro1-/- MEFs, genetically encoded H2O2 biosensor HyPer7, PRX2/PRX3 oxidation state, focal adhesion immunofluorescence, rotenone treatment","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells, biosensor-based subcellular redox mapping, multiple orthogonal readouts; single lab","pmids":["33341544"],"is_preprint":false},{"year":2018,"finding":"Mitochondrial calcium uniporter (MCU) interacts with Miro1 through MCU's N-terminal domain, which traverses the outer mitochondrial membrane. This MCU–Miro1 interaction is required for Miro1-directed mitochondrial movement; Miro1 is a novel component of the MCU complex.","method":"Co-IP, domain deletion/mutation of MCU N-terminus, mitochondrial transport imaging in neurons, MCU overexpression/knockdown","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying interaction domain, transport functional assay; single lab","pmids":["29686046"],"is_preprint":false},{"year":2020,"finding":"Miro1-mutant neurons (R272Q) show increased MERC number (vs. decreased in fibroblasts), altered mitochondrial dynamics, increased sensitivity to Ca2+ stress, reduced mitochondrial clearance, and blocked autophagic flux, indicating that mutant Miro1 disrupts ER-mitochondrial tethering and autophagic flux in neurons.","method":"iPSC-derived PD patient neurons (Miro1-R272Q), live-cell imaging, immunocytochemistry for MERCs, mitophagy assays, western blotting for autophagy markers","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived iPSC neurons, multiple imaging and biochemical methods; single lab","pmids":["32280985"],"is_preprint":false},{"year":2020,"finding":"Peroxisomal fission is negatively regulated by Miro1 and Miro2 via suppression of Drp1-dependent fission, shared with their function on mitochondria. Peroxisomal targeting of Miro is regulated by the first GTPase domain and is mediated through an interaction of its transmembrane domain with the peroxisomal membrane protein chaperone Pex19.","method":"Miro1/2 KO cells, Drp1 dependence assays, Pex19 interaction studies, peroxisome morphology analysis by microscopy","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO phenotype, interaction mapping, Drp1 dependence test; single lab","pmids":["31894645"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of the human Miro1 N-terminal GTPase domain (1.7Å) reveals it bound to GTP in a non-catalytic configuration. Two conserved surfaces ('SELFYY' and 'ITIP' motifs) are identified as potential dimerization or binding partner interfaces. SAXS data model the intact soluble HsMiro1/2 as a crescent-shaped assembly.","method":"X-ray crystallography (1.7Å, PDB 6D71), SAXS of intact soluble domain","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure at 1.7Å with SAXS validation; single lab but high-resolution structural data","pmids":["33132189"],"is_preprint":false},{"year":2023,"finding":"MIRO-1 (C. elegans ortholog) interacts with VDAC-1 at the outer mitochondrial membrane; this interaction depends on residue E473 of MIRO-1 and K163 of VDAC-1. The MIRO-1 E473G point mutation disrupts this interaction and reduces mitochondrial membrane potential.","method":"Co-IP, point mutagenesis (E473G in MIRO-1, K163 in VDAC-1), mitochondrial membrane potential measurements in C. elegans","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mutagenesis validation, functional membrane potential readout; C. elegans ortholog, single lab","pmids":["37306041"],"is_preprint":false},{"year":2022,"finding":"PD-associated Miro1 R272Q mutation (located in the first EF-hand/calcium-binding domain) causes mitochondrial fragmentation, reduced cristae and ATP5A, impaired mitochondrial calcium buffering (phenocopied by MCU inhibition), reduced mitochondrial respiration, and defective dopamine neurotransmitter regulation via monoamine oxidase in dopaminergic neurons.","method":"CRISPR gene-edited iPSC (heterozygous R272Q), iPSC-derived dopaminergic neurons, mitophagy assays (CCCP), Ca2+ imaging (Thapsigargin), Seahorse respirometry, catecholamine neurotransmitter assays","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic iPSC-derived neurons, multiple functional readouts; single lab","pmids":["36533136"],"is_preprint":false},{"year":2022,"finding":"The formin mDia2 stabilizes MIRO1 protein in cancer-associated fibroblasts. Loss of mDia2 or MIRO1 reduces peripheral mitochondrial positioning, lowers peripheral ATP levels and CAF-tumor contact-site ATP, causes metabolic dysfunction, and suppresses secretion of protumorigenic proteins, implicating an activin A–mDia2–MIRO1 axis in CAF function.","method":"mDia2/MIRO1 knockdown in fibroblasts and CAFs, mitochondrial localization imaging, ATP biosensor, proteomic secretome analysis, in vivo tumor models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD of both components, in vivo validation, ATP biosensor; single lab","pmids":["35997559"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of the MIRO1–TRAK1 complex reveals TRAK1 binds MIRO1 at two distinct sites: TRAK1(569-623) binds in a cleft between the nGTPase and first EF-hand pair; TRAK1(425-428) binds a pocket between the second EF-hand pair and cGTPase. The complex dimerizes via interactions through the second EF-hand pair and cGTPase. Both sites are required for TRAK1 mitochondrial localization, validated by mutagenesis and binding assays.","method":"Cryo-EM structure determination, mutagenesis of both binding sites, binding assays, cell-based mitochondrial localization assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with mutagenesis and binding assay validation; multiple orthogonal methods in single rigorous study","pmids":["40615373"],"is_preprint":false},{"year":2025,"finding":"A conserved region in the flexible linker between the Ubl and RING0 domains of Parkin is indispensable for Parkin–Miro1 interaction and is required for Miro1 ubiquitination. This linker region explains fast kinetics of Miro1 ubiquitination and provides a biochemical basis for Miro1-dependent Parkin recruitment to the outer mitochondrial membrane prior to activation.","method":"Recombinant protein interaction assays, mutagenesis of Parkin linker region, in vitro ubiquitination assays, cellular Parkin recruitment assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, mutagenesis, and cellular validation; multiple orthogonal methods","pmids":["40576561"],"is_preprint":false},{"year":2025,"finding":"Patient-derived iPSC neurons and knock-in mice expressing Miro1 p.R272Q (murine orthologue p.R285Q) show increased oxidative stress, disrupted mitochondrial bioenergetics, elevated α-synuclein levels, calcium-dependent calpain activation with α-synuclein cleavage, and significant dopaminergic neuron loss with phospho-α-synuclein accumulation in striatum.","method":"iPSC-derived midbrain organoids and dopaminergic neurons (isogenic controls), Miro1 p.R285Q knock-in mice, metabolic assays, Ca2+ measurements, calpain activity assays, immunohistochemistry, behavioral analysis","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient iPSC neurons + isogenic controls + knock-in mouse model; multiple orthogonal methods across two independent model systems","pmids":["39913247"],"is_preprint":false},{"year":2025,"finding":"Miro1 accumulates in skeletal muscle of obese/T2D mice and humans due to impaired insulin-mediated AKT–Miro1 interaction at the outer mitochondrial membrane. Muscle-specific Miro1 deletion improves insulin action and mitochondrial oxidative capacity. Exercise training reduces skeletal muscle Miro1 accumulation in T2D patients, correlating with improved insulin sensitivity.","method":"Human clinical exercise intervention (randomized, N=24 T2D patients), muscle-specific Miro1 KO mice, AKT-Miro1 interaction assays, metabolic/insulin sensitivity measurements, Seahorse respirometry","journal":"medRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human RCT + mouse KO mechanistic validation; preprint, pending peer review","pmids":["41030931"],"is_preprint":true},{"year":2025,"finding":"MIRO1 maintains mitochondrial cristae integrity and ETC complex I activity and super-complex formation in vascular smooth muscle cells (VSMCs), enabling PDGF-stimulated ATP production for G1/S cell-cycle progression. A MIRO1 mutant lacking EF hands (Ca2+-sensing) only partially rescues these effects, indicating that both mitochondrial positioning (EF-hand-dependent) and cristae integrity (EF-hand-independent) contribute to VSMC proliferation.","method":"Smooth-muscle-specific Miro1 KO mice, VSMC KD, mitochondrial cristae electron microscopy, ETC complex activity assays, cell-cycle analysis, ATP measurements, human coronary artery VSMC knockdown","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mouse KO + human cell KD + multiple mitochondrial functional assays; preprint, pending peer review","pmids":["39185180"],"is_preprint":true},{"year":2025,"finding":"MIRO1 is required for dynamic increases in mitochondria-ER contact sites (MERCs) during G1/S cell-cycle progression. MIRO1 interacts with GRP75 (detected by proximity-ligation assay with VDAC1-IP3R at MERCs). MIRO1 EF-hand and transmembrane domain mutants fail to rescue cell proliferation or MERC formation. MIRO1 deficiency blocks G1/S transition and impairs ER Ca2+ release and mitochondrial Ca2+ uptake.","method":"Fibroblast-specific Miro1 KO, proximity-ligation assay, split-GFP ER/mitochondria contact assay, mitochondrial Ca2+/ATP measurements, MIRO1 domain mutants, cell cycle analysis","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model, proximity-ligation and split-GFP structural contact assays, domain mutagenesis; single lab","pmids":["40214436"],"is_preprint":false},{"year":2016,"finding":"In Xenopus embryos, the mitochondrial GTPase Rhot1 regulates microtubule-dependent mitochondrial trafficking required for aggregation of germinal granule components during primordial germ cell formation. Dominant-negative Rhot1ΔC (lacking transmembrane domain) inhibited germline-mitochondria aggregation and prevented germinal granule component aggregation, reducing PGC number.","method":"Dominant-negative Rhot1ΔC expression in Xenopus embryos, fluorescence imaging of germline mitochondria and germinal granules, PGC counting","journal":"Development, growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative approach in Xenopus ortholog, direct imaging of mitochondrial and granule trafficking; single lab","pmids":["27585825"],"is_preprint":false},{"year":2022,"finding":"Miro1 depletion in mouse oocytes via oocyte-specific KO disrupts mitochondrial spatial distribution (causing perinuclear and cortical aggregates) and reduces polar body extrusion by ~20%, implicating Miro1 as a mitochondrial adaptor setting mitochondrial distribution in oocytes.","method":"Oocyte-specific Miro1 conditional KO, live imaging of mitochondrial distribution, polar body extrusion quantification, embryo development in vitro","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined subcellular and functional phenotype; single lab","pmids":["36325364"],"is_preprint":false},{"year":2025,"finding":"MIRO1 associates with cytoskeleton and cell cycle proteins (by mass spectrometry), regulates dynein motor for MTOC dynamics at the GV stage (determining meiotic resumption), and regulates Aurora A and KIF11 for meiotic spindle assembly in porcine and mouse oocytes. MIRO1 also interacts with DRP1, Parkin, and LAMP2 for mitochondrial dynamics and mitophagy during oocyte meiosis.","method":"Mass spectrometry, siRNA/morpholino knockdown, rescue by Miro1 mRNA injection, immunofluorescence of spindle/MTOC/mitochondria in mouse and porcine oocytes","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry interaction data, rescue experiments, dual-species validation; single lab","pmids":["39815032"],"is_preprint":false},{"year":2021,"finding":"Miro1 conditional deletion in parvalbumin (PV+) interneurons in mice impairs Miro1-directed mitochondrial trafficking, alters mitochondrial distribution and axonal arborization of PV+ interneurons, increases hippocampal γ-oscillation frequency ex vivo, and promotes anxiolysis, without abolishing PV+ interneuron-mediated inhibition.","method":"Cre-mediated Miro1 KO in PV+ interneurons, live and fixed imaging, ex vivo hippocampal γ-oscillation recording, behavioral assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO, neurophysiology and imaging readouts; single lab","pmids":["34190042"],"is_preprint":false},{"year":2025,"finding":"Miro1 N-terminal GTPase domain activity is required for ER-mitochondria contact (ERMC) formation in differentiating neurons. Glucocorticoid-induced downregulation of Miro1 impairs ERMC formation and increases Drp1 Ser616 phosphorylation (promoting fission). Miro1 overexpression restores ERMC formation, increases mitochondrial Ca2+ uptake, and reduces Drp1-Ser616 phosphorylation.","method":"AAV-mediated expression of Miro1 WT and N-terminal GTPase mutant (P26V) in hippocampal neurons of prenatally stressed mice, hiPSC-derived neurons, Drp1 phosphorylation analysis, ERMC imaging","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific mutant with functional readout, dual mouse and human iPSC models; single lab","pmids":["40176126"],"is_preprint":false},{"year":2014,"finding":"CK2β (regulatory subunit of Casein Kinase II) promotes PINK1-cytoplasmic isoform (PINK1-cyto)/Parkin-mediated degradation of Miro1, independent of CK2α. CK2β facilitates direct interaction between PINK1-cyto and Miro1 as shown by co-immunoprecipitation.","method":"HEK293 cell transfection, Western blot for Miro1 protein levels, co-immunoprecipitation","journal":"Sheng wu yi xue gong cheng xue za zhi","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP and western blot; single lab, limited methods, no independent replication","pmids":["25868250"],"is_preprint":false}],"current_model":"RHOT1/Miro1 is an outer mitochondrial membrane GTPase that serves as a master scaffold linking mitochondria to microtubule motor proteins (kinesin KIF5, dynein) and actin motor myosin XIX via adaptor proteins TRAK1/TRAK2 (Grif-1); its two EF-hand calcium-binding domains act as cytosolic Ca2+ sensors that halt mitochondrial transport upon Ca2+ binding, enabling activity-dependent mitochondrial positioning at synapses, growth cones, and sites of high energy demand. Miro1 also regulates mitochondria-ER contact sites (MERCs) and mitochondrial Ca2+ handling, promotes peroxisome motility via splice variants that interact with Pex19, and is a direct ubiquitination substrate of the PINK1/Parkin pathway during mitophagy—with a specific substrate-interaction region in Parkin's Ubl-RING0 linker directing Miro1 ubiquitination at multiple lysine residues; dysregulation of Miro1 removal from damaged mitochondria is a common feature of Parkinson's disease, and PD-associated Miro1 mutations (especially R272Q in the EF-hand domain) impair calcium buffering, disrupt mitochondrial bioenergetics, elevate α-synuclein, and cause dopaminergic neuron loss in patient iPSC models and knock-in mice."},"narrative":{"mechanistic_narrative":"RHOT1/Miro1 is an outer mitochondrial membrane Rho-GTPase that functions as the master scaffold coupling mitochondria to cytoskeletal motors and thereby controls activity-dependent organelle positioning at sites of high energy demand [PMID:19249275, PMID:28615318]. Through GTPase-dependent recruitment of the TRAK adaptors (Grif-1/TRAK2, TRAK1), Miro1 links mitochondria to kinesin (KIF5) and dynein motors to drive bidirectional axonal and microtubule-based transport, with cryo-EM resolving TRAK1 docking at two sites spanning the nGTPase, EF-hand pairs, and cGTPase, and the first GTPase domain dictating transport directionality [PMID:19249275, PMID:19103291, PMID:24092329, PMID:24492963, PMID:40615373, PMID:32637409]. Miro1 also serves as the mitochondrial receptor for the actin motor myosin XIX, binding its C-terminal tail in a GTPase-state-dependent manner and stabilizing the motor [PMID:30111583]. Its two EF-hand calcium-binding domains act as cytosolic Ca2+ sensors that disrupt the Miro1/KIF5/tubulin complex to halt mitochondrial movement and drive a fission-independent mitochondrial shape transition required for mitophagy initiation, enabling repositioning of mitochondria at presynaptic terminals and astrocytic processes for homeostatic plasticity and Ca2+ signaling [PMID:19249275, PMID:29694881, PMID:28039205, PMID:26631479]. Beyond transport, Miro1 organizes mitochondria-ER contact sites and mitochondrial Ca2+ handling, restrains MFN-mediated outer-membrane fusion under elevated Ca2+, and through splice variants and a transmembrane-domain interaction with Pex19 also localizes to peroxisomes to regulate their motility and Drp1-dependent fission [PMID:40214436, PMID:34431132, PMID:29222186, PMID:31894645]. By positioning mitochondria peripherally, Miro1 establishes local ATP and H2O2 gradients that support actin dynamics, focal adhesion assembly, and cell migration [PMID:28615318, PMID:33341544]. Miro1 is a direct substrate of the PINK1/Parkin mitophagy pathway: activated Parkin ubiquitylates Miro1 at multiple conserved lysines in a PINK1-Ser65-phosphorylation-dependent manner, with a conserved Parkin Ubl-RING0 linker region mediating the Miro1 interaction and rapid ubiquitination needed for Parkin recruitment to damaged mitochondria [PMID:24647965, PMID:40576561]. Failure to remove Miro1 from depolarized mitochondria blocks mitophagy and is a common feature of Parkinson's disease patient cells, and the PD-associated EF-hand mutation R272Q impairs calcium buffering, disrupts bioenergetics and ER-mitochondria tethering, elevates α-synuclein, and causes dopaminergic neuron loss in iPSC and knock-in mouse models [PMID:31564441, PMID:32280985, PMID:36533136, PMID:39913247].","teleology":[{"year":2008,"claim":"Established how Miro1 physically engages the transport machinery, showing it recruits the TRAK/Grif-1 adaptor to mitochondria in a GTPase-dependent fashion to drive anterograde movement.","evidence":"Reciprocal co-IP, GTPase-domain mutants, and live neuronal imaging","pmids":["19103291"],"confidence":"High","gaps":["Did not resolve the kinesin contact directly","Structural basis of adaptor recruitment unknown"]},{"year":2009,"claim":"Defined Miro1's central function as a Ca2+-gated linker between mitochondria and KIF5 kinesin, explaining how neuronal activity halts mitochondrial transport.","evidence":"EF-hand dominant-negative mutants, Co-IP with KIF5, live imaging under glutamate/NMDA stimulation","pmids":["19249275"],"confidence":"High","gaps":["Molecular mechanism of Ca2+-induced complex disassembly not structurally resolved","Did not address retrograde/dynein engagement"]},{"year":2013,"claim":"Extended the adaptor complex, placing DISC1 with TRAK1 and Miro1 to specify anterograde transport and linking it to a disease variant.","evidence":"Co-IP of DISC1–TRAK1–Miro1 complex and live axon imaging","pmids":["24092329"],"confidence":"Medium","gaps":["Single lab","Direct vs. indirect DISC1–Miro1 contact not distinguished"]},{"year":2014,"claim":"Identified Miro1 as a direct PINK1/Parkin mitophagy substrate, mapping the ubiquitylation sites and establishing PINK1-dependent Parkin activation as the trigger for its removal.","evidence":"In vitro E3 ligase reconstitution with recombinant Parkin/Miro1, mass spectrometry site mapping, mutagenesis","pmids":["24647965"],"confidence":"High","gaps":["Did not define Parkin's Miro1-binding region","Cellular kinetics of removal not addressed"]},{"year":2014,"claim":"Demonstrated the physiological necessity of Miro1-directed transport in vivo, showing axonal mitochondrial depletion drives motor neuron disease while respiration and Ca2+ inhibition are preserved.","evidence":"Neuron-specific Miro1 knockout mice with axonal transport and respiratory assays","pmids":["25136135"],"confidence":"High","gaps":["Separation of anterograde vs. retrograde roles incomplete","Cell-autonomous vs. circuit effects not fully dissected"]},{"year":2014,"claim":"Broadened Miro1's roles beyond neurons to dynein-based redistribution in lymphocytes and intercellular mitochondrial transfer from stem cells, indicating motor-coupling functions in immune and regenerative contexts.","evidence":"siRNA knockdown with dynein co-IP and migration assays; Miro1 gain/loss-of-function with mitochondrial transfer tracking and in vivo injury models","pmids":["24492963","24431222"],"confidence":"Medium","gaps":["Single labs","Mechanism of intercellular transfer (tunneling nanotubes vs. vesicles) not resolved"]},{"year":2017,"claim":"Connected Miro1-dependent mitochondrial positioning to local energy supply, showing peripheral ATP gradients drive actin dynamics, focal adhesions, and cell migration.","evidence":"Miro1-/- MEFs with ATP:ADP biosensor, focal adhesion imaging, migration assays","pmids":["28615318"],"confidence":"High","gaps":["Did not establish the redox component","Generalizability beyond fibroblasts untested"]},{"year":2017,"claim":"Showed Miro1 levels are pathologically degraded in disease, with ALS mutant SOD1 lowering Miro1 via PINK1/Parkin (not Ca2+) to impair axonal transport.","evidence":"ALS-SOD1 transfection in cortical/motor neurons, Miro1 quantification, rescue by Miro1 OE or PINK1 ablation","pmids":["28973175"],"confidence":"Medium","gaps":["Single lab","Direct link to motor neuron death in vivo not shown"]},{"year":2018,"claim":"Expanded the motor repertoire by identifying Miro1 as the GTPase-state-regulated mitochondrial receptor for the actin motor myosin XIX, with motor stability dependent on Miro1.","evidence":"Proximity labeling, direct pulldown binding assays, in vivo recruitment, GTPase mutants","pmids":["30111583"],"confidence":"High","gaps":["Functional consequence of actin-based transport in vivo limited","Coordination with microtubule motors unresolved"]},{"year":2018,"claim":"Resolved Miro1's EF-hand-driven mechanism for a fission-independent mitochondrial shape transition (MiST) required for mitophagy, and linked Miro1 to Ca2+ uptake machinery via the MCU complex.","evidence":"EF-hand mutagenesis with Ca2+ manipulation and mitophagy assays; MCU N-terminal domain mapping with co-IP and transport assays","pmids":["29694881","29686046"],"confidence":"High","gaps":["Structural basis of MiST not defined","MCU–Miro1 interaction single lab"]},{"year":2018,"claim":"Defined Miro1's dual-organelle role, showing splice variants and a transmembrane Pex19 interaction target Miro1 to peroxisomes to drive their microtubule-based motility via TRAK2.","evidence":"Splice variant characterization, Pex19 interaction studies, knockdown/re-expression, live peroxisome tracking and modelling","pmids":["29222186","29364559"],"confidence":"High","gaps":["Relative contribution of variants vs. transmembrane targeting partly overlapping","Regulation of organelle choice unknown"]},{"year":2016,"claim":"Showed Miro1's EF-hand Ca2+ sensing controls activity-dependent mitochondrial positioning at synapses and in astrocytic processes, coupling organelle placement to local Ca2+ signaling and homeostatic plasticity.","evidence":"EF-hand mutant neurons and astrocytes with genetically encoded Ca2+ indicators, live imaging, electrophysiology in slices","pmids":["28039205","26631479"],"confidence":"High","gaps":["Molecular targets downstream of repositioning incomplete","In vivo circuit consequences not addressed"]},{"year":2019,"claim":"Established defective Miro1 removal as a convergent Parkinson's disease feature, with PINK1, Parkin, and LRRK2 required for its clearance and a small molecule rescuing mitophagy and neurodegeneration.","evidence":"Patient fibroblast depolarization assays, iPSC neurons, Drosophila PD models, small-molecule screen","pmids":["31564441"],"confidence":"High","gaps":["Mechanism of LRRK2 involvement not detailed","Clinical translation of small molecule untested"]},{"year":2019,"claim":"Linked RHOT1 coding mutations to PD pathophysiology through reduced ER-mitochondria contacts and disrupted Ca2+ homeostasis in patient cells.","evidence":"Patient fibroblast live imaging, MERC immunocytochemistry, Ca2+ and mitophagy assays","pmids":["31303019"],"confidence":"Medium","gaps":["Single lab","Cell-type specificity (fibroblast vs. neuron) discrepancies"]},{"year":2020,"claim":"Deepened the regulatory and functional map: Miro1 restrains MFN-mediated fusion under Ca2+, peripheral positioning shapes H2O2 redox gradients for focal adhesions, and a PINK1-regulated Ser156 phosphorylation tunes Miro1 stability and degradation.","evidence":"Co-IP/BioID with EF-hand mutants for MFN; Miro1-/- MEFs with HyPer7 redox biosensor; CRISPR S156A iPSC dopaminergic neurons with respirometry","pmids":["34431132","33341544","35455950"],"confidence":"Medium","gaps":["Single labs","Kinase responsible for Ser156 not definitively assigned"]},{"year":2020,"claim":"Modeled the PD-associated EF-hand mutation R272Q, showing it impairs calcium buffering, disrupts MERCs and autophagic flux, and impairs dopaminergic mitochondrial function.","evidence":"Isogenic CRISPR R272Q iPSC dopaminergic neurons with Ca2+ imaging, respirometry, mitophagy and neurotransmitter assays","pmids":["32280985","36533136"],"confidence":"Medium","gaps":["Single lab","Mechanistic basis of opposite MERC change in neurons vs. fibroblasts unresolved"]},{"year":2020,"claim":"Provided the first high-resolution structural view, capturing the N-terminal GTPase domain bound to GTP in a non-catalytic state and modeling the intact protein as a crescent assembly.","evidence":"1.7 Å X-ray crystallography (PDB 6D71) and SAXS","pmids":["33132189"],"confidence":"High","gaps":["Full-length membrane-anchored structure absent","Functional consequence of GTP non-catalytic state unclear"]},{"year":2023,"claim":"Identified a VDAC-1 interaction at the outer membrane (in the C. elegans ortholog) coupling Miro1 to mitochondrial membrane potential.","evidence":"Co-IP and point mutagenesis (MIRO-1 E473G, VDAC-1 K163) with membrane potential measurements in C. elegans","pmids":["37306041"],"confidence":"Medium","gaps":["Ortholog system","Human relevance and mechanism of potential maintenance untested"]},{"year":2025,"claim":"Resolved the architecture of the Miro1–TRAK1 transport complex and the biochemical basis of Parkin recruitment, defining two TRAK1 docking sites and an essential Parkin Ubl-RING0 linker for Miro1 ubiquitination.","evidence":"Cryo-EM of MIRO1–TRAK1 with mutagenesis and localization assays; recombinant interaction and ubiquitination assays mapping the Parkin linker","pmids":["40615373","40576561"],"confidence":"High","gaps":["Full motor-complex (kinesin/dynein) architecture not resolved","How Ca2+ remodels these interfaces structurally unaddressed"]},{"year":2025,"claim":"Provided in vivo disease causality for the EF-hand mutation, with R272Q/R285Q knock-in mice and patient iPSC neurons showing oxidative stress, bioenergetic failure, calpain-dependent α-synuclein cleavage, and dopaminergic neuron loss.","evidence":"iPSC midbrain organoids/neurons with isogenic controls and Miro1 p.R285Q knock-in mice with metabolic, Ca2+, calpain, and histological assays","pmids":["39913247"],"confidence":"High","gaps":["Mechanistic link from calpain activation to α-synuclein pathology incomplete","Therapeutic targeting not tested"]},{"year":2025,"claim":"Extended Miro1 function to cell-cycle and proliferative control, showing it drives dynamic MERC formation (via GRP75) and cristae/ETC integrity required for G1/S progression in fibroblasts and vascular smooth muscle.","evidence":"Fibroblast and smooth-muscle Miro1 KO, proximity-ligation/split-GFP MERC assays, domain mutants, cristae EM and ETC activity assays (one preprint)","pmids":["40214436","39185180"],"confidence":"Medium","gaps":["One source is a preprint","EF-hand-independent cristae role mechanistically undefined"]},{"year":null,"claim":"How Ca2+ binding to the EF-hands is structurally transmitted to remodel motor-adaptor interfaces, and how Miro1 dynamically partitions its scaffolding among kinesin, dynein, myosin XIX, MERC, and mitophagy functions, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length membrane-anchored structure with bound motors","Mechanism coordinating competing scaffold functions unknown","Regulation of organelle (mitochondria vs. peroxisome) and motor selection undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[1,9,18,24,38]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,10,11,12,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,9,13,28]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,7,9,28]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,4,35]},{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[13,14,23]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10,15,17]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,9,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[33]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,26,30]}],"complexes":["MCU complex","MIRO1–TRAK1 transport complex"],"partners":["TRAK1","TRAK2","KIF5","MYO19","PARK2","PINK1","MCU","MFN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IXI2","full_name":"Mitochondrial Rho GTPase 1","aliases":["Rac-GTP-binding protein-like protein","Ras homolog gene family member T1"],"length_aa":618,"mass_kda":70.8,"function":"Atypical mitochondrial nucleoside-triphosphatase (NTPase) involved in mitochondrial trafficking (PubMed:12482879, PubMed:16630562, PubMed:22396657, PubMed:30513825). Probably involved in control of anterograde transport of mitochondria and their subcellular distribution (PubMed:12482879, PubMed:16630562, PubMed:22396657). Promotes mitochondrial fission during high calcium conditions (PubMed:27716788). Can hydrolyze GTP, ATP and UTP (PubMed:30513825)","subcellular_location":"Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q8IXI2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RHOT1","classification":"Not Classified","n_dependent_lines":36,"n_total_lines":1208,"dependency_fraction":0.029801324503311258},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"IPO5","stoichiometry":0.2},{"gene":"TOMM20A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RHOT1","total_profiled":1310},"omim":[{"mim_id":"613889","title":"RAS HOMOLOG GENE FAMILY, MEMBER T2; RHOT2","url":"https://www.omim.org/entry/613889"},{"mim_id":"613888","title":"RAS HOMOLOG GENE FAMILY, MEMBER T1; RHOT1","url":"https://www.omim.org/entry/613888"},{"mim_id":"605704","title":"VAMP-ASSOCIATED PROTEIN B AND C; VAPB","url":"https://www.omim.org/entry/605704"},{"mim_id":"300364","title":"ARMADILLO REPEAT-CONTAINING PROTEIN, X-LINKED 3; ARMCX3","url":"https://www.omim.org/entry/300364"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Ca2+ binding to Miro1's EF-hand domains (at micromolar levels) inhibits this linkage, halting mitochondrial movement. Mutation of EF-hand domains to prevent Ca2+ binding blocked glutamate/NMDA receptor-induced mitochondrial stopping but preserved basal motility.\",\n      \"method\": \"Dominant-negative EF-hand mutant expression, live-cell imaging, neuronal activity manipulation (glutamate/NMDA stimulation), Co-IP of Miro1 with KIF5\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (mutagenesis, live imaging, co-IP), replicated across conditions, foundational mechanistic study\",\n      \"pmids\": [\"19249275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Miro1 recruits the adaptor protein Grif-1 (TRAK2) to mitochondria in a GTPase-dependent manner. This Miro1–Grif-1 complex promotes anterograde transport of mitochondria into neuronal processes. Mutation of Miro1's first GTPase domain impairs Grif-1 recruitment and alters mitochondrial distribution and morphology.\",\n      \"method\": \"Co-IP, overexpression/dominant-negative constructs, live neuronal imaging, subcellular fractionation\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, GTPase mutant analysis, live imaging; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"19103291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Miro1 knockout in mice depletes mitochondria from corticospinal tract axons and causes progressive upper motor neuron disease and developmental defects in cranial motor nuclei. Miro1-deficient neurons show defective retrograde axonal mitochondrial transport but retain normal mitochondrial respiratory function and Ca2+-mediated inhibition of movement.\",\n      \"method\": \"Neuron-specific Miro1 knockout mice, immunofluorescence, neurological behavioral analysis, axonal transport assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse model with defined neurological phenotype, multiple readouts including transport and respiratory function\",\n      \"pmids\": [\"25136135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Parkin ubiquitylates Miro1 at conserved lysine residues (K153, K230, K235, K330, K572) in a PINK1 phosphorylation-dependent manner. PINK1 phosphorylation of Parkin at Ser65 is required for substrate (Miro1) ubiquitylation. Miro1 serves as a direct substrate of activated Parkin E3 ligase.\",\n      \"method\": \"In vitro E3 ligase reconstitution assay with recombinant full-length untagged Parkin and Miro1, mass spectrometry identification of ubiquitylation sites, mutagenesis of Parkin catalytic cysteine and disease variants\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant proteins, mass spectrometry site mapping, mutagenesis validation, multiple orthogonal assays\",\n      \"pmids\": [\"24647965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Miro1 deletion in mouse embryonic fibroblasts restricts mitochondria to the perinuclear area, depleting peripheral ATP:ADP ratios, and thereby impairs actin dynamics, lamellipodia protrusion, focal adhesion assembly/stability, and cell migration (both collective and single-cell).\",\n      \"method\": \"Miro1-/- MEF cells, genetically encoded ATP:ADP biosensor (PercevalHR), live-cell imaging, focal adhesion immunofluorescence, migration assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells with defined phenotype, multiple orthogonal methods (biosensor, imaging, functional assays), causal link between positioning and energy gradients\",\n      \"pmids\": [\"28615318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DISC1 forms a complex with TRAK1 (trafficking kinesin-binding protein 1) and Miro1 on mitochondria and specifically promotes anterograde axonal mitochondrial transport. A rare DISC1 variant (37W) impairs anterograde transport and redistributes mitochondrial DISC1.\",\n      \"method\": \"Co-IP (DISC1–TRAK1–Miro1 complex), live neuronal axon imaging, disease-variant functional analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP establishing complex membership, live imaging showing anterograde transport role; single lab\",\n      \"pmids\": [\"24092329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Miro1 regulates intercellular mitochondrial transfer from mesenchymal stem cells (MSC) to epithelial cells. Miro1 overexpression in MSC enhances mitochondrial transfer and therapeutic rescue of epithelial injury; Miro1 knockdown reduces transfer efficacy.\",\n      \"method\": \"Miro1 overexpression/knockdown in MSC, fluorescent mitochondria tracking, mouse models of airway injury and allergic inflammation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with direct mitochondrial transfer quantification, in vivo validation, single lab\",\n      \"pmids\": [\"24431222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Miro-1 associates with the dynein motor complex on lymphocyte mitochondria, and Miro-1 silencing impairs mitochondrial redistribution to the MTOC during chemokine CXCL12-induced polarization, reducing myosin II activation and actin polymerization, thereby impairing lymphocyte adhesion and migration.\",\n      \"method\": \"Miro-1 siRNA knockdown, co-IP with dynein, live-cell imaging, flow adhesion assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying dynein interaction, KD with defined migratory phenotype, single lab\",\n      \"pmids\": [\"24492963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ALS mutant SOD1 reduces endogenous Miro1 protein levels through PINK1/Parkin-dependent degradation (not via elevated cytosolic Ca2+), causing impaired anterograde axonal mitochondrial transport. Miro1 overexpression or PINK1 ablation rescues this transport deficit.\",\n      \"method\": \"ALS mutant SOD1 transfection in cortical and motor neurons, Miro1 protein level quantification, mitochondrial transport imaging, Parkin-dependence shown by co-expression experiments, Ca2+ measurements\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiments (Miro1 OE, PINK1 KO), negative result for Ca2+ mechanism, multiple neuron types; single lab\",\n      \"pmids\": [\"28973175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Miro1 and Miro2 are identified as mitochondrial receptors for myosin XIX (Myo19). Miro1 binds directly to the C-terminal tail of Myo19, recruits it to mitochondria in vivo, and this recruitment is regulated by the GTPase state of Miro1's N-terminal Rho-GTPase domain. Myo19 protein stability depends on its association with Miro1/2.\",\n      \"method\": \"Proximity labeling, direct binding assays (pulldown), in vivo recruitment assays, Miro1/2 knockdown and overexpression, protein stability analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding demonstrated, proximity labeling, in vivo recruitment, GTPase-state dependence by mutagenesis; multiple orthogonal methods\",\n      \"pmids\": [\"30111583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Miro1, through its EF-hand domain 1, senses cytosolic Ca2+ elevation and mediates a distinct mitochondrial shape transition (MiST) that is independent of classical fission or swelling. Ca2+-dependent disruption of the Miro1/KIF5B/tubulin complex is controlled by the EF1 domain. Miro1-dependent MiST is required for autophagy/mitophagy initiation.\",\n      \"method\": \"EF-hand mutant expression, live-cell Ca2+ manipulation, GPCR activation, morphometric analysis, Miro1 KO cells, autophagy/mitophagy assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — EF-hand mutagenesis, multiple cell types, Ca2+ manipulation with functional readout, mitophagy assays; multiple orthogonal methods\",\n      \"pmids\": [\"29694881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Miro1 Ca2+-sensing (EF-hand) function is required for activity-dependent repositioning of mitochondria to presynaptic terminals during prolonged neuronal activity. This repositioning decreases presynaptic Ca2+ signals and neurotransmitter release, enabling homeostatic plasticity.\",\n      \"method\": \"Miro1 EF-hand mutant neurons, genetically encoded presynaptic Ca2+ indicator SyGCaMP5, live imaging, electrophysiology\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EF-hand mutant analysis, genetically encoded biosensors, live imaging, functional synaptic readout; multiple methods\",\n      \"pmids\": [\"28039205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Miro1 Ca2+-sensing EF-hand domains regulate activity-dependent mitochondrial confinement in astrocytic processes near synapses. Miro1-mediated mitochondrial positioning reciprocally regulates intracellular Ca2+ signaling levels in astrocytic processes.\",\n      \"method\": \"EF-hand mutant Miro1 expression, live-cell confocal microscopy in rat organotypic hippocampal slices, Ca2+ imaging\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EF-hand mutagenesis in organotypic slices, live Ca2+ imaging, activity-driven mitochondrial positioning quantified; multiple methods\",\n      \"pmids\": [\"26631479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Three splice variants of human Miro1 (var2, var3, var4) containing sequence insertions upstream of the transmembrane domain localize to peroxisomes, recognized by the cytosolic receptor Pex19. Peroxisomal Miro1 variants act as adaptors linking peroxisomes to TRAK2-containing microtubule transport complexes, promoting long-range peroxisome movement.\",\n      \"method\": \"Identification and characterization of splice variants, peroxisome localization by immunofluorescence, Pex19 interaction studies, MIRO1 knockdown/re-expression, live-cell peroxisome tracking\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — splice variant characterization, organelle localization, receptor interaction, rescue experiments; multiple orthogonal methods\",\n      \"pmids\": [\"29222186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Miro1 localizes to peroxisomes (in addition to mitochondria) and regulates microtubule-dependent peroxisome motility. Miro1's transmembrane domain mediates interaction with the peroxisomal membrane chaperone Pex19. Miro1-mediated pulling forces contribute to peroxisome membrane elongation and proliferation.\",\n      \"method\": \"Microscopy, live-cell imaging, mathematical modelling, peroxisome-targeted Miro1 fusion protein, Miro1 knockdown\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments, functional Miro1 fusion construct, quantitative motility analysis; single lab\",\n      \"pmids\": [\"29364559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Parkinson's disease patient fibroblasts (>94%), Miro1 fails to be removed from depolarized mitochondria, blocking initiation of mitophagy. PINK1, Parkin, and LRRK2 are required molecular helpers for Miro1 removal from dysfunctional mitochondria. A small molecule that reduces Miro1 levels repairs this defect and rescues locomotor deficits and dopaminergic neurodegeneration in patient-derived neurons and fly PD models.\",\n      \"method\": \"Biochemical Miro1 depolarization assay in patient fibroblasts, iPSC-derived neurons, Drosophila PD models, small molecule screen\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient fibroblasts (broad cohort), iPSC neurons, in vivo fly rescue; multiple systems and methods\",\n      \"pmids\": [\"31564441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RHOT1 mutations in PD patients (het c.815G>A; het c.1348C>T) reduce mitochondrial-ER contact sites (MERCs) and disrupt Ca2+ homeostasis in patient-derived fibroblasts, impairing energy metabolism and increasing mitophagy.\",\n      \"method\": \"Patient fibroblast live-cell imaging, immunocytochemistry for MERCs, Ca2+ homeostasis assays, mitophagy quantification\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cellular models, multiple functional readouts, live imaging; single lab\",\n      \"pmids\": [\"31303019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Miro1 Ser156 phosphorylation is a PINK1-regulated modification affecting Miro1 steady-state protein levels and degradation during mitophagy. A phospho-null S156A mutation causes significant depletion of Miro1 protein, impairs further degradation upon mitophagy induction, leads to slightly elongated mitochondria, and reduces mitochondrial oxygen consumption with depletion of OXPHOS complexes III and V in human dopaminergic neurons.\",\n      \"method\": \"CRISPR/Cas9 gene-edited iPSC (homozygous S156A), differentiation to dopaminergic neurons, mitophagy induction (CCCP), immunoblotting, Seahorse respirometry, live-cell mitochondrial movement imaging\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene-edited human iPSC neurons, multiple functional readouts; single lab, single publication\",\n      \"pmids\": [\"35455950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DISC1 promotes anterograde mitochondrial transport in a manner dependent on Miro1's GTP-bound (active) state at the first GTPase domain. The first GTPase domain of Miro1 determines the direction of mitochondrial transport.\",\n      \"method\": \"Miro1 GTPase domain mutants, live neuronal imaging, DISC1 co-expression experiments\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GTPase domain mutagenesis, live imaging of directional transport; single lab\",\n      \"pmids\": [\"32637409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Miro1 interacts with Mitofusin (MFN) and inhibits MFN-mediated mitochondrial outer membrane fusion in response to elevated mitochondrial Ca2+ concentration. This inhibition requires Miro1's EF-hand domain 1. Lowering mitochondrial Ca2+ or knocking down Miro1/2 promotes network fusion.\",\n      \"method\": \"Co-IP, proximity labeling proteomics (BioID), EF-hand mutant expression, ectopic MFN expression, MCU inhibitor treatment, Miro1/2 knockdown\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and proximity labeling establishing interaction, EF-hand mutagenesis for Ca2+ dependence; single lab\",\n      \"pmids\": [\"34431132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Miro1 deletion in Miro1-/- MEFs restricts subcellular H2O2 to the perinuclear area and prevents peripheral oxidation of cytosolic peroxiredoxin 2 (PRX2) after mitochondrial complex I inhibition. Local H2O2 levels correlate with focal adhesion size and abundance; Miro1-/- cells have smaller focal adhesions with reduced vinculin and p130Cas phosphorylation.\",\n      \"method\": \"Miro1-/- MEFs, genetically encoded H2O2 biosensor HyPer7, PRX2/PRX3 oxidation state, focal adhesion immunofluorescence, rotenone treatment\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells, biosensor-based subcellular redox mapping, multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"33341544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mitochondrial calcium uniporter (MCU) interacts with Miro1 through MCU's N-terminal domain, which traverses the outer mitochondrial membrane. This MCU–Miro1 interaction is required for Miro1-directed mitochondrial movement; Miro1 is a novel component of the MCU complex.\",\n      \"method\": \"Co-IP, domain deletion/mutation of MCU N-terminus, mitochondrial transport imaging in neurons, MCU overexpression/knockdown\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying interaction domain, transport functional assay; single lab\",\n      \"pmids\": [\"29686046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Miro1-mutant neurons (R272Q) show increased MERC number (vs. decreased in fibroblasts), altered mitochondrial dynamics, increased sensitivity to Ca2+ stress, reduced mitochondrial clearance, and blocked autophagic flux, indicating that mutant Miro1 disrupts ER-mitochondrial tethering and autophagic flux in neurons.\",\n      \"method\": \"iPSC-derived PD patient neurons (Miro1-R272Q), live-cell imaging, immunocytochemistry for MERCs, mitophagy assays, western blotting for autophagy markers\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived iPSC neurons, multiple imaging and biochemical methods; single lab\",\n      \"pmids\": [\"32280985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Peroxisomal fission is negatively regulated by Miro1 and Miro2 via suppression of Drp1-dependent fission, shared with their function on mitochondria. Peroxisomal targeting of Miro is regulated by the first GTPase domain and is mediated through an interaction of its transmembrane domain with the peroxisomal membrane protein chaperone Pex19.\",\n      \"method\": \"Miro1/2 KO cells, Drp1 dependence assays, Pex19 interaction studies, peroxisome morphology analysis by microscopy\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO phenotype, interaction mapping, Drp1 dependence test; single lab\",\n      \"pmids\": [\"31894645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of the human Miro1 N-terminal GTPase domain (1.7Å) reveals it bound to GTP in a non-catalytic configuration. Two conserved surfaces ('SELFYY' and 'ITIP' motifs) are identified as potential dimerization or binding partner interfaces. SAXS data model the intact soluble HsMiro1/2 as a crescent-shaped assembly.\",\n      \"method\": \"X-ray crystallography (1.7Å, PDB 6D71), SAXS of intact soluble domain\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure at 1.7Å with SAXS validation; single lab but high-resolution structural data\",\n      \"pmids\": [\"33132189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MIRO-1 (C. elegans ortholog) interacts with VDAC-1 at the outer mitochondrial membrane; this interaction depends on residue E473 of MIRO-1 and K163 of VDAC-1. The MIRO-1 E473G point mutation disrupts this interaction and reduces mitochondrial membrane potential.\",\n      \"method\": \"Co-IP, point mutagenesis (E473G in MIRO-1, K163 in VDAC-1), mitochondrial membrane potential measurements in C. elegans\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mutagenesis validation, functional membrane potential readout; C. elegans ortholog, single lab\",\n      \"pmids\": [\"37306041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PD-associated Miro1 R272Q mutation (located in the first EF-hand/calcium-binding domain) causes mitochondrial fragmentation, reduced cristae and ATP5A, impaired mitochondrial calcium buffering (phenocopied by MCU inhibition), reduced mitochondrial respiration, and defective dopamine neurotransmitter regulation via monoamine oxidase in dopaminergic neurons.\",\n      \"method\": \"CRISPR gene-edited iPSC (heterozygous R272Q), iPSC-derived dopaminergic neurons, mitophagy assays (CCCP), Ca2+ imaging (Thapsigargin), Seahorse respirometry, catecholamine neurotransmitter assays\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic iPSC-derived neurons, multiple functional readouts; single lab\",\n      \"pmids\": [\"36533136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The formin mDia2 stabilizes MIRO1 protein in cancer-associated fibroblasts. Loss of mDia2 or MIRO1 reduces peripheral mitochondrial positioning, lowers peripheral ATP levels and CAF-tumor contact-site ATP, causes metabolic dysfunction, and suppresses secretion of protumorigenic proteins, implicating an activin A–mDia2–MIRO1 axis in CAF function.\",\n      \"method\": \"mDia2/MIRO1 knockdown in fibroblasts and CAFs, mitochondrial localization imaging, ATP biosensor, proteomic secretome analysis, in vivo tumor models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD of both components, in vivo validation, ATP biosensor; single lab\",\n      \"pmids\": [\"35997559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of the MIRO1–TRAK1 complex reveals TRAK1 binds MIRO1 at two distinct sites: TRAK1(569-623) binds in a cleft between the nGTPase and first EF-hand pair; TRAK1(425-428) binds a pocket between the second EF-hand pair and cGTPase. The complex dimerizes via interactions through the second EF-hand pair and cGTPase. Both sites are required for TRAK1 mitochondrial localization, validated by mutagenesis and binding assays.\",\n      \"method\": \"Cryo-EM structure determination, mutagenesis of both binding sites, binding assays, cell-based mitochondrial localization assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with mutagenesis and binding assay validation; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"40615373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A conserved region in the flexible linker between the Ubl and RING0 domains of Parkin is indispensable for Parkin–Miro1 interaction and is required for Miro1 ubiquitination. This linker region explains fast kinetics of Miro1 ubiquitination and provides a biochemical basis for Miro1-dependent Parkin recruitment to the outer mitochondrial membrane prior to activation.\",\n      \"method\": \"Recombinant protein interaction assays, mutagenesis of Parkin linker region, in vitro ubiquitination assays, cellular Parkin recruitment assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, mutagenesis, and cellular validation; multiple orthogonal methods\",\n      \"pmids\": [\"40576561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Patient-derived iPSC neurons and knock-in mice expressing Miro1 p.R272Q (murine orthologue p.R285Q) show increased oxidative stress, disrupted mitochondrial bioenergetics, elevated α-synuclein levels, calcium-dependent calpain activation with α-synuclein cleavage, and significant dopaminergic neuron loss with phospho-α-synuclein accumulation in striatum.\",\n      \"method\": \"iPSC-derived midbrain organoids and dopaminergic neurons (isogenic controls), Miro1 p.R285Q knock-in mice, metabolic assays, Ca2+ measurements, calpain activity assays, immunohistochemistry, behavioral analysis\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient iPSC neurons + isogenic controls + knock-in mouse model; multiple orthogonal methods across two independent model systems\",\n      \"pmids\": [\"39913247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Miro1 accumulates in skeletal muscle of obese/T2D mice and humans due to impaired insulin-mediated AKT–Miro1 interaction at the outer mitochondrial membrane. Muscle-specific Miro1 deletion improves insulin action and mitochondrial oxidative capacity. Exercise training reduces skeletal muscle Miro1 accumulation in T2D patients, correlating with improved insulin sensitivity.\",\n      \"method\": \"Human clinical exercise intervention (randomized, N=24 T2D patients), muscle-specific Miro1 KO mice, AKT-Miro1 interaction assays, metabolic/insulin sensitivity measurements, Seahorse respirometry\",\n      \"journal\": \"medRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human RCT + mouse KO mechanistic validation; preprint, pending peer review\",\n      \"pmids\": [\"41030931\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MIRO1 maintains mitochondrial cristae integrity and ETC complex I activity and super-complex formation in vascular smooth muscle cells (VSMCs), enabling PDGF-stimulated ATP production for G1/S cell-cycle progression. A MIRO1 mutant lacking EF hands (Ca2+-sensing) only partially rescues these effects, indicating that both mitochondrial positioning (EF-hand-dependent) and cristae integrity (EF-hand-independent) contribute to VSMC proliferation.\",\n      \"method\": \"Smooth-muscle-specific Miro1 KO mice, VSMC KD, mitochondrial cristae electron microscopy, ETC complex activity assays, cell-cycle analysis, ATP measurements, human coronary artery VSMC knockdown\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mouse KO + human cell KD + multiple mitochondrial functional assays; preprint, pending peer review\",\n      \"pmids\": [\"39185180\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MIRO1 is required for dynamic increases in mitochondria-ER contact sites (MERCs) during G1/S cell-cycle progression. MIRO1 interacts with GRP75 (detected by proximity-ligation assay with VDAC1-IP3R at MERCs). MIRO1 EF-hand and transmembrane domain mutants fail to rescue cell proliferation or MERC formation. MIRO1 deficiency blocks G1/S transition and impairs ER Ca2+ release and mitochondrial Ca2+ uptake.\",\n      \"method\": \"Fibroblast-specific Miro1 KO, proximity-ligation assay, split-GFP ER/mitochondria contact assay, mitochondrial Ca2+/ATP measurements, MIRO1 domain mutants, cell cycle analysis\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model, proximity-ligation and split-GFP structural contact assays, domain mutagenesis; single lab\",\n      \"pmids\": [\"40214436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Xenopus embryos, the mitochondrial GTPase Rhot1 regulates microtubule-dependent mitochondrial trafficking required for aggregation of germinal granule components during primordial germ cell formation. Dominant-negative Rhot1ΔC (lacking transmembrane domain) inhibited germline-mitochondria aggregation and prevented germinal granule component aggregation, reducing PGC number.\",\n      \"method\": \"Dominant-negative Rhot1ΔC expression in Xenopus embryos, fluorescence imaging of germline mitochondria and germinal granules, PGC counting\",\n      \"journal\": \"Development, growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative approach in Xenopus ortholog, direct imaging of mitochondrial and granule trafficking; single lab\",\n      \"pmids\": [\"27585825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Miro1 depletion in mouse oocytes via oocyte-specific KO disrupts mitochondrial spatial distribution (causing perinuclear and cortical aggregates) and reduces polar body extrusion by ~20%, implicating Miro1 as a mitochondrial adaptor setting mitochondrial distribution in oocytes.\",\n      \"method\": \"Oocyte-specific Miro1 conditional KO, live imaging of mitochondrial distribution, polar body extrusion quantification, embryo development in vitro\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined subcellular and functional phenotype; single lab\",\n      \"pmids\": [\"36325364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MIRO1 associates with cytoskeleton and cell cycle proteins (by mass spectrometry), regulates dynein motor for MTOC dynamics at the GV stage (determining meiotic resumption), and regulates Aurora A and KIF11 for meiotic spindle assembly in porcine and mouse oocytes. MIRO1 also interacts with DRP1, Parkin, and LAMP2 for mitochondrial dynamics and mitophagy during oocyte meiosis.\",\n      \"method\": \"Mass spectrometry, siRNA/morpholino knockdown, rescue by Miro1 mRNA injection, immunofluorescence of spindle/MTOC/mitochondria in mouse and porcine oocytes\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry interaction data, rescue experiments, dual-species validation; single lab\",\n      \"pmids\": [\"39815032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Miro1 conditional deletion in parvalbumin (PV+) interneurons in mice impairs Miro1-directed mitochondrial trafficking, alters mitochondrial distribution and axonal arborization of PV+ interneurons, increases hippocampal γ-oscillation frequency ex vivo, and promotes anxiolysis, without abolishing PV+ interneuron-mediated inhibition.\",\n      \"method\": \"Cre-mediated Miro1 KO in PV+ interneurons, live and fixed imaging, ex vivo hippocampal γ-oscillation recording, behavioral assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO, neurophysiology and imaging readouts; single lab\",\n      \"pmids\": [\"34190042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Miro1 N-terminal GTPase domain activity is required for ER-mitochondria contact (ERMC) formation in differentiating neurons. Glucocorticoid-induced downregulation of Miro1 impairs ERMC formation and increases Drp1 Ser616 phosphorylation (promoting fission). Miro1 overexpression restores ERMC formation, increases mitochondrial Ca2+ uptake, and reduces Drp1-Ser616 phosphorylation.\",\n      \"method\": \"AAV-mediated expression of Miro1 WT and N-terminal GTPase mutant (P26V) in hippocampal neurons of prenatally stressed mice, hiPSC-derived neurons, Drp1 phosphorylation analysis, ERMC imaging\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific mutant with functional readout, dual mouse and human iPSC models; single lab\",\n      \"pmids\": [\"40176126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CK2β (regulatory subunit of Casein Kinase II) promotes PINK1-cytoplasmic isoform (PINK1-cyto)/Parkin-mediated degradation of Miro1, independent of CK2α. CK2β facilitates direct interaction between PINK1-cyto and Miro1 as shown by co-immunoprecipitation.\",\n      \"method\": \"HEK293 cell transfection, Western blot for Miro1 protein levels, co-immunoprecipitation\",\n      \"journal\": \"Sheng wu yi xue gong cheng xue za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP and western blot; single lab, limited methods, no independent replication\",\n      \"pmids\": [\"25868250\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RHOT1/Miro1 is an outer mitochondrial membrane GTPase that serves as a master scaffold linking mitochondria to microtubule motor proteins (kinesin KIF5, dynein) and actin motor myosin XIX via adaptor proteins TRAK1/TRAK2 (Grif-1); its two EF-hand calcium-binding domains act as cytosolic Ca2+ sensors that halt mitochondrial transport upon Ca2+ binding, enabling activity-dependent mitochondrial positioning at synapses, growth cones, and sites of high energy demand. Miro1 also regulates mitochondria-ER contact sites (MERCs) and mitochondrial Ca2+ handling, promotes peroxisome motility via splice variants that interact with Pex19, and is a direct ubiquitination substrate of the PINK1/Parkin pathway during mitophagy—with a specific substrate-interaction region in Parkin's Ubl-RING0 linker directing Miro1 ubiquitination at multiple lysine residues; dysregulation of Miro1 removal from damaged mitochondria is a common feature of Parkinson's disease, and PD-associated Miro1 mutations (especially R272Q in the EF-hand domain) impair calcium buffering, disrupt mitochondrial bioenergetics, elevate α-synuclein, and cause dopaminergic neuron loss in patient iPSC models and knock-in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RHOT1/Miro1 is an outer mitochondrial membrane Rho-GTPase that functions as the master scaffold coupling mitochondria to cytoskeletal motors and thereby controls activity-dependent organelle positioning at sites of high energy demand [#0, #4]. Through GTPase-dependent recruitment of the TRAK adaptors (Grif-1/TRAK2, TRAK1), Miro1 links mitochondria to kinesin (KIF5) and dynein motors to drive bidirectional axonal and microtubule-based transport, with cryo-EM resolving TRAK1 docking at two sites spanning the nGTPase, EF-hand pairs, and cGTPase, and the first GTPase domain dictating transport directionality [#0, #1, #5, #7, #28, #18]. Miro1 also serves as the mitochondrial receptor for the actin motor myosin XIX, binding its C-terminal tail in a GTPase-state-dependent manner and stabilizing the motor [#9]. Its two EF-hand calcium-binding domains act as cytosolic Ca2+ sensors that disrupt the Miro1/KIF5/tubulin complex to halt mitochondrial movement and drive a fission-independent mitochondrial shape transition required for mitophagy initiation, enabling repositioning of mitochondria at presynaptic terminals and astrocytic processes for homeostatic plasticity and Ca2+ signaling [#0, #10, #11, #12]. Beyond transport, Miro1 organizes mitochondria-ER contact sites and mitochondrial Ca2+ handling, restrains MFN-mediated outer-membrane fusion under elevated Ca2+, and through splice variants and a transmembrane-domain interaction with Pex19 also localizes to peroxisomes to regulate their motility and Drp1-dependent fission [#33, #19, #13, #23]. By positioning mitochondria peripherally, Miro1 establishes local ATP and H2O2 gradients that support actin dynamics, focal adhesion assembly, and cell migration [#4, #20]. Miro1 is a direct substrate of the PINK1/Parkin mitophagy pathway: activated Parkin ubiquitylates Miro1 at multiple conserved lysines in a PINK1-Ser65-phosphorylation-dependent manner, with a conserved Parkin Ubl-RING0 linker region mediating the Miro1 interaction and rapid ubiquitination needed for Parkin recruitment to damaged mitochondria [#3, #29]. Failure to remove Miro1 from depolarized mitochondria blocks mitophagy and is a common feature of Parkinson's disease patient cells, and the PD-associated EF-hand mutation R272Q impairs calcium buffering, disrupts bioenergetics and ER-mitochondria tethering, elevates \\u03b1-synuclein, and causes dopaminergic neuron loss in iPSC and knock-in mouse models [#15, #22, #26, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established how Miro1 physically engages the transport machinery, showing it recruits the TRAK/Grif-1 adaptor to mitochondria in a GTPase-dependent fashion to drive anterograde movement.\",\n      \"evidence\": \"Reciprocal co-IP, GTPase-domain mutants, and live neuronal imaging\",\n      \"pmids\": [\"19103291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the kinesin contact directly\", \"Structural basis of adaptor recruitment unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined Miro1's central function as a Ca2+-gated linker between mitochondria and KIF5 kinesin, explaining how neuronal activity halts mitochondrial transport.\",\n      \"evidence\": \"EF-hand dominant-negative mutants, Co-IP with KIF5, live imaging under glutamate/NMDA stimulation\",\n      \"pmids\": [\"19249275\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of Ca2+-induced complex disassembly not structurally resolved\", \"Did not address retrograde/dynein engagement\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the adaptor complex, placing DISC1 with TRAK1 and Miro1 to specify anterograde transport and linking it to a disease variant.\",\n      \"evidence\": \"Co-IP of DISC1–TRAK1–Miro1 complex and live axon imaging\",\n      \"pmids\": [\"24092329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct vs. indirect DISC1–Miro1 contact not distinguished\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified Miro1 as a direct PINK1/Parkin mitophagy substrate, mapping the ubiquitylation sites and establishing PINK1-dependent Parkin activation as the trigger for its removal.\",\n      \"evidence\": \"In vitro E3 ligase reconstitution with recombinant Parkin/Miro1, mass spectrometry site mapping, mutagenesis\",\n      \"pmids\": [\"24647965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define Parkin's Miro1-binding region\", \"Cellular kinetics of removal not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated the physiological necessity of Miro1-directed transport in vivo, showing axonal mitochondrial depletion drives motor neuron disease while respiration and Ca2+ inhibition are preserved.\",\n      \"evidence\": \"Neuron-specific Miro1 knockout mice with axonal transport and respiratory assays\",\n      \"pmids\": [\"25136135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Separation of anterograde vs. retrograde roles incomplete\", \"Cell-autonomous vs. circuit effects not fully dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Broadened Miro1's roles beyond neurons to dynein-based redistribution in lymphocytes and intercellular mitochondrial transfer from stem cells, indicating motor-coupling functions in immune and regenerative contexts.\",\n      \"evidence\": \"siRNA knockdown with dynein co-IP and migration assays; Miro1 gain/loss-of-function with mitochondrial transfer tracking and in vivo injury models\",\n      \"pmids\": [\"24492963\", \"24431222\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single labs\", \"Mechanism of intercellular transfer (tunneling nanotubes vs. vesicles) not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected Miro1-dependent mitochondrial positioning to local energy supply, showing peripheral ATP gradients drive actin dynamics, focal adhesions, and cell migration.\",\n      \"evidence\": \"Miro1-/- MEFs with ATP:ADP biosensor, focal adhesion imaging, migration assays\",\n      \"pmids\": [\"28615318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the redox component\", \"Generalizability beyond fibroblasts untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed Miro1 levels are pathologically degraded in disease, with ALS mutant SOD1 lowering Miro1 via PINK1/Parkin (not Ca2+) to impair axonal transport.\",\n      \"evidence\": \"ALS-SOD1 transfection in cortical/motor neurons, Miro1 quantification, rescue by Miro1 OE or PINK1 ablation\",\n      \"pmids\": [\"28973175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct link to motor neuron death in vivo not shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded the motor repertoire by identifying Miro1 as the GTPase-state-regulated mitochondrial receptor for the actin motor myosin XIX, with motor stability dependent on Miro1.\",\n      \"evidence\": \"Proximity labeling, direct pulldown binding assays, in vivo recruitment, GTPase mutants\",\n      \"pmids\": [\"30111583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of actin-based transport in vivo limited\", \"Coordination with microtubule motors unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved Miro1's EF-hand-driven mechanism for a fission-independent mitochondrial shape transition (MiST) required for mitophagy, and linked Miro1 to Ca2+ uptake machinery via the MCU complex.\",\n      \"evidence\": \"EF-hand mutagenesis with Ca2+ manipulation and mitophagy assays; MCU N-terminal domain mapping with co-IP and transport assays\",\n      \"pmids\": [\"29694881\", \"29686046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MiST not defined\", \"MCU–Miro1 interaction single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined Miro1's dual-organelle role, showing splice variants and a transmembrane Pex19 interaction target Miro1 to peroxisomes to drive their microtubule-based motility via TRAK2.\",\n      \"evidence\": \"Splice variant characterization, Pex19 interaction studies, knockdown/re-expression, live peroxisome tracking and modelling\",\n      \"pmids\": [\"29222186\", \"29364559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of variants vs. transmembrane targeting partly overlapping\", \"Regulation of organelle choice unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed Miro1's EF-hand Ca2+ sensing controls activity-dependent mitochondrial positioning at synapses and in astrocytic processes, coupling organelle placement to local Ca2+ signaling and homeostatic plasticity.\",\n      \"evidence\": \"EF-hand mutant neurons and astrocytes with genetically encoded Ca2+ indicators, live imaging, electrophysiology in slices\",\n      \"pmids\": [\"28039205\", \"26631479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets downstream of repositioning incomplete\", \"In vivo circuit consequences not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established defective Miro1 removal as a convergent Parkinson's disease feature, with PINK1, Parkin, and LRRK2 required for its clearance and a small molecule rescuing mitophagy and neurodegeneration.\",\n      \"evidence\": \"Patient fibroblast depolarization assays, iPSC neurons, Drosophila PD models, small-molecule screen\",\n      \"pmids\": [\"31564441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of LRRK2 involvement not detailed\", \"Clinical translation of small molecule untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked RHOT1 coding mutations to PD pathophysiology through reduced ER-mitochondria contacts and disrupted Ca2+ homeostasis in patient cells.\",\n      \"evidence\": \"Patient fibroblast live imaging, MERC immunocytochemistry, Ca2+ and mitophagy assays\",\n      \"pmids\": [\"31303019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Cell-type specificity (fibroblast vs. neuron) discrepancies\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Deepened the regulatory and functional map: Miro1 restrains MFN-mediated fusion under Ca2+, peripheral positioning shapes H2O2 redox gradients for focal adhesions, and a PINK1-regulated Ser156 phosphorylation tunes Miro1 stability and degradation.\",\n      \"evidence\": \"Co-IP/BioID with EF-hand mutants for MFN; Miro1-/- MEFs with HyPer7 redox biosensor; CRISPR S156A iPSC dopaminergic neurons with respirometry\",\n      \"pmids\": [\"34431132\", \"33341544\", \"35455950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single labs\", \"Kinase responsible for Ser156 not definitively assigned\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Modeled the PD-associated EF-hand mutation R272Q, showing it impairs calcium buffering, disrupts MERCs and autophagic flux, and impairs dopaminergic mitochondrial function.\",\n      \"evidence\": \"Isogenic CRISPR R272Q iPSC dopaminergic neurons with Ca2+ imaging, respirometry, mitophagy and neurotransmitter assays\",\n      \"pmids\": [\"32280985\", \"36533136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanistic basis of opposite MERC change in neurons vs. fibroblasts unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the first high-resolution structural view, capturing the N-terminal GTPase domain bound to GTP in a non-catalytic state and modeling the intact protein as a crescent assembly.\",\n      \"evidence\": \"1.7 Å X-ray crystallography (PDB 6D71) and SAXS\",\n      \"pmids\": [\"33132189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length membrane-anchored structure absent\", \"Functional consequence of GTP non-catalytic state unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a VDAC-1 interaction at the outer membrane (in the C. elegans ortholog) coupling Miro1 to mitochondrial membrane potential.\",\n      \"evidence\": \"Co-IP and point mutagenesis (MIRO-1 E473G, VDAC-1 K163) with membrane potential measurements in C. elegans\",\n      \"pmids\": [\"37306041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog system\", \"Human relevance and mechanism of potential maintenance untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the architecture of the Miro1–TRAK1 transport complex and the biochemical basis of Parkin recruitment, defining two TRAK1 docking sites and an essential Parkin Ubl-RING0 linker for Miro1 ubiquitination.\",\n      \"evidence\": \"Cryo-EM of MIRO1–TRAK1 with mutagenesis and localization assays; recombinant interaction and ubiquitination assays mapping the Parkin linker\",\n      \"pmids\": [\"40615373\", \"40576561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full motor-complex (kinesin/dynein) architecture not resolved\", \"How Ca2+ remodels these interfaces structurally unaddressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided in vivo disease causality for the EF-hand mutation, with R272Q/R285Q knock-in mice and patient iPSC neurons showing oxidative stress, bioenergetic failure, calpain-dependent α-synuclein cleavage, and dopaminergic neuron loss.\",\n      \"evidence\": \"iPSC midbrain organoids/neurons with isogenic controls and Miro1 p.R285Q knock-in mice with metabolic, Ca2+, calpain, and histological assays\",\n      \"pmids\": [\"39913247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link from calpain activation to α-synuclein pathology incomplete\", \"Therapeutic targeting not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended Miro1 function to cell-cycle and proliferative control, showing it drives dynamic MERC formation (via GRP75) and cristae/ETC integrity required for G1/S progression in fibroblasts and vascular smooth muscle.\",\n      \"evidence\": \"Fibroblast and smooth-muscle Miro1 KO, proximity-ligation/split-GFP MERC assays, domain mutants, cristae EM and ETC activity assays (one preprint)\",\n      \"pmids\": [\"40214436\", \"39185180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"One source is a preprint\", \"EF-hand-independent cristae role mechanistically undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Ca2+ binding to the EF-hands is structurally transmitted to remodel motor-adaptor interfaces, and how Miro1 dynamically partitions its scaffolding among kinesin, dynein, myosin XIX, MERC, and mitophagy functions, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length membrane-anchored structure with bound motors\", \"Mechanism coordinating competing scaffold functions unknown\", \"Regulation of organelle (mitochondria vs. peroxisome) and motor selection undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [1, 9, 18, 24, 38]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 10, 11, 12, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 9, 13, 28]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 7, 9, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [0, 9, 25, 31]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 4, 35]},\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [13, 14, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10, 15, 17]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 9, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [33]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 26, 30]}\n    ],\n    \"complexes\": [\"MCU complex\", \"MIRO1–TRAK1 transport complex\"],\n    \"partners\": [\"TRAK1\", \"TRAK2\", \"KIF5\", \"MYO19\", \"PARK2\", \"PINK1\", \"MCU\", \"MFN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}