{"gene":"STOML2","run_date":"2026-04-28T21:42:57","timeline":{"discoveries":[{"year":2000,"finding":"SLP-2 (STOML2) was cloned and characterized as a novel stomatin homologue present in erythrocytes and other tissues. It partitions into both Triton X-100-soluble and -insoluble pools, is fully extractable by NaOH (unlike stomatin, indicating no direct membrane bilayer insertion), and interacts with the peripheral erythrocyte cytoskeleton. It lacks the N-terminal hydrophobic domain found in other stomatin family members.","method":"cDNA cloning, Northern/Western blot, subcellular fractionation (Triton X-100, NaOH extraction), SDS-PAGE, expression in COS cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical fractionation and localization experiments, single lab, moderate orthogonal methods","pmids":["10713127"],"is_preprint":false},{"year":2008,"finding":"SLP-2 is strongly associated with the mitochondrial inner membrane and physically interacts with prohibitins (PHB1/PHB2). Depletion of SLP-2 in HeLa cells leads to increased proteolysis of prohibitins and subunits of respiratory chain complexes I and IV, indicating SLP-2 regulates the stability of these mitochondrial proteins.","method":"Proteomic approaches, co-immunoprecipitation, siRNA knockdown, subcellular fractionation, Western blot","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction demonstrated, loss-of-function with specific molecular phenotype (proteolysis of defined substrates), replicated proteomic identification","pmids":["18339324"],"is_preprint":false},{"year":2009,"finding":"SLP-2 is required for stress-induced mitochondrial hyperfusion (SIMH). In the absence of SLP-2, long-form OPA1 (L-OPA1) is lost and SIMH is prevented. SIMH requires L-OPA1, MFN1, and SLP-2 but is independent of MFN2, BAX/BAK, and prohibitins. SIMH is accompanied by increased mitochondrial ATP production and represents a pro-survival adaptive response.","method":"siRNA knockdown, live-cell imaging of mitochondrial morphology, epistasis analysis (double knockdown/knockout), ATP measurement, UV/actinomycin D stress models","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple defined components, clean KO/KD with specific morphological and biochemical phenotypes, highly cited foundational study","pmids":["19360003"],"is_preprint":false},{"year":2009,"finding":"SLP-2 modulates mitochondrial sodium-calcium exchange. SLP-2 depletion increases rates of Ca2+ extrusion from mitochondria via the mitochondrial Na+/Ca2+ exchanger (mNCX); this effect is abolished by Na+ removal or CGP-37157 (mNCX inhibitor). SLP-2 overexpression prolongs mitochondrial Ca2+ retention, and SLP-2 depletion increases cytosolic Ca2+ elevations, demonstrating SLP-2 negatively regulates mNCX activity.","method":"siRNA knockdown, SLP-2 overexpression, mitochondrial and cytosolic Ca2+ imaging, pharmacological inhibition (CGP-37157, Na+ removal), permeabilized cell assays","journal":"Cell calcium","confidence":"High","confidence_rationale":"Tier 1-2 — gain- and loss-of-function with pharmacological dissection of specific transporter, mechanistic specificity confirmed by Na+ removal and inhibitor experiments","pmids":["19944461"],"is_preprint":false},{"year":2009,"finding":"SLP-2 localizes to mitochondria, maintains mitochondrial membrane potential (MMP) and ATP production, and its knockdown inhibits cell motility and proliferation and enhances chemosensitivity in tumor cells.","method":"siRNA knockdown, immunofluorescence (mitochondrial localization), MMP assay, ATP measurement, cell motility assays, cell proliferation assays","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2-3 — localization confirmed, functional consequences measured, single lab","pmids":["19597348"],"is_preprint":false},{"year":2013,"finding":"In C. elegans, the STOML2 ortholog STL-1 (Stomatin-like 1) is transcriptionally induced by SKN-1/Nrf in response to anoxia and facilitates mitochondrial fusion dynamics during reoxygenation. This places STOML2 downstream of the oxidative stress response factor SKN-1 in controlling mitochondrial fission/fusion balance.","method":"Genetic epistasis in C. elegans, live imaging of mitochondrial morphology, GFP reporter assays, mutant analysis (egl-9, hif-1, skn-1, stl-1)","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in C. elegans ortholog, multiple mutant combinations, functional mitochondrial imaging; ortholog inference","pmids":["24385935"],"is_preprint":false},{"year":2017,"finding":"SLP-2 physically interacts with Parkin at mitochondria. Co-immunoprecipitation and proximity ligation assays demonstrated endogenous interaction. SLP-2 and Parkin genetically interact: SLP-2 overexpression rescues Parkin-deficiency phenotypes (reduced complex I activity, abnormal mitochondrial morphology, loss of dopaminergic neurons, reduced ATP, motor dysfunction) in iPSC-derived neurons and Drosophila. SLP-2 is placed epistatic to Parkin in maintaining mitochondrial respiratory chain function.","method":"Co-immunoprecipitation, proximity ligation assay (endogenous proteins), siRNA knockdown, iPSC-derived neuron models, Drosophila genetic rescue experiments, respiratory chain complex I activity assay, mitochondrial network imaging","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction by two orthogonal methods, genetic epistasis in two independent model systems (neurons and Drosophila), multiple functional readouts","pmids":["28379402"],"is_preprint":false},{"year":2021,"finding":"STOML2 interacts with and stabilizes PINK1 under cellular stress conditions, amplifying PINK1-Parkin-mediated mitophagy. HIF-1α transcriptionally upregulates STOML2 expression. The STOML2-PINK1 interaction was demonstrated by co-immunoprecipitation.","method":"Co-immunoprecipitation, laser confocal microscopy, flow cytometry, transmission electron microscopy, Western blot, ChIP assay, luciferase reporter assay","journal":"Journal of hematology & oncology","confidence":"High","confidence_rationale":"Tier 2 — direct protein-protein interaction by Co-IP, transcriptional regulation confirmed by ChIP and luciferase reporter, multiple orthogonal methods","pmids":["33446239"],"is_preprint":false},{"year":2021,"finding":"STOML2 interacts with prohibitin (PHB) and activates the MAPK signaling pathway (RAF1, MEK1/2, ERK1/2 phosphorylation) to promote colorectal cancer proliferation. The STOML2-PHB interaction was confirmed by co-immunoprecipitation and immunofluorescence co-localization. Knockdown of STOML2 downregulates MAPK pathway phosphorylation.","method":"Yeast two-hybrid screening, co-immunoprecipitation, immunofluorescence, Western blot (phospho-RAF1/MEK/ERK), siRNA knockdown, organoid culture, orthotopic tumor model","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2-3 — interaction validated by Co-IP and co-localization, pathway effect shown by Western blot, single lab","pmids":["34781982"],"is_preprint":false},{"year":2023,"finding":"STOML2 stabilizes PARL (presenilin-associated rhomboid-like protease) at the mitochondrial inner membrane, preventing PARL-mediated PINK1 degradation and thereby restricting PINK1-dependent mitophagy. In pancreatic cancer, this STOML2-PARL-PINK1 axis controls mitochondrial mass and chemosensitivity.","method":"Tissue microarray, siRNA/overexpression, Western blot, co-immunoprecipitation (STOML2-PARL interaction), flow cytometry, mitochondrial mass measurement, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP demonstrating STOML2-PARL interaction, functional consequences on PINK1 degradation measured, single lab","pmids":["36906621"],"is_preprint":false},{"year":2024,"finding":"STOML2 physically binds TRADD protein and activates NF-κB signaling, resulting in upregulation of CCND1, VEGF, and PD-L1 in colorectal cancer, thereby promoting proliferation, angiogenesis, and immune escape.","method":"Co-immunoprecipitation (STOML2-TRADD binding), siRNA/overexpression, Western blot, in vitro and in vivo tumor models","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP for interaction, functional pathway readouts, single lab","pmids":["38214751"],"is_preprint":false},{"year":2024,"finding":"The Parkin-SLP-2 interaction is mediated primarily through the Parkin RING0 domain. PD-associated PRKN missense mutations that overlap with SLP-2 binding sites reduce the Parkin-SLP-2 interaction. Delivery of the isolated Parkin RING0 domain or a derived mini-peptide rescues mitochondrial dysfunction in Parkin-deficient neuroblastoma cells and iPSC-derived neurons.","method":"Proximity ligation assay (quantitative), domain mapping (truncation constructs), computational structural modeling (crystal structure-based), high-resolution respirometry, immunofluorescence, live imaging, iPSC-derived neurons","journal":"Journal of translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 — structural prediction validated by domain mapping and functional rescue, interaction quantified in disease-relevant neurons, multiple orthogonal methods","pmids":["38229174"],"is_preprint":false},{"year":2025,"finding":"Under hypoxia, HIF-1α transcriptionally induces STOML2 expression. STOML2 then translocates to the outer mitochondrial membrane and participates in PGAM5 cleavage, initiating PINK1-dependent mitophagy as a neuroprotective response. Knockdown of HIF-1α, STOML2, or PGAM5 inhibits this mitophagy and worsens neuronal injury.","method":"siRNA knockdown of HIF-1α/STOML2/PGAM5, overexpression, immunofluorescence (mitochondrial localization), mitophagy assays, neuronal injury assays, in vivo mouse model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — epistatic pathway dissected by triple knockdown, localization confirmed; single lab, peer-reviewed","pmids":["41723145"],"is_preprint":false},{"year":2026,"finding":"STOML2 interacts with the mitochondrial Na+/Ca2+ exchanger NCLX to support mitochondrial Ca2+ efflux and metabolic stability. STOML2 depletion impairs oxidative phosphorylation, elevates mitochondrial ROS, and promotes chondrocyte senescence and ferroptotic cell death in osteoarthritis models.","method":"Co-immunoprecipitation (STOML2-NCLX), siRNA knockdown, STOML2 overexpression, mitochondrial Ca2+ measurement, OCR measurement, ROS assay, intra-articular delivery in rat OA model","journal":"Genetics research","confidence":"Medium","confidence_rationale":"Tier 2-3 — STOML2-NCLX interaction by Co-IP, functional Ca2+ measurements, in vivo validation; single lab","pmids":["41995387"],"is_preprint":false},{"year":2026,"finding":"STOML2 and PHB form a functional axis that maintains ERK/MAPK signaling activity and pluripotency in human pluripotent stem cells. STOML2 knockdown reduces OCT4, NANOG, PHB, and phosphorylated ERK while increasing differentiation markers, demonstrating STOML2 is required for hPSC self-renewal through the PHB-ERK pathway.","method":"shRNA knockdown, transcriptomic profiling (RNA-seq), Western blot (phospho-ERK), immunofluorescence, flow cytometry","journal":"International journal of stem cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — loss-of-function with specific pluripotency and signaling phenotypes, pathway confirmed by phospho-protein measurement; single lab","pmids":["41709508"],"is_preprint":false},{"year":2025,"finding":"SLP-2 overexpression protects against alpha-synuclein-induced mitochondrial dysfunction and dopaminergic neuron loss. SLP-2 levels are reduced in human PD brains and in an A53T alpha-synuclein mouse model. SLP-2 overexpression in iPSC-derived neurons improves mitochondrial function, reduces oxidative stress, and prevents alpha-synuclein-mitochondria interactions. SLP-2 depletion exacerbates degeneration in mouse and Drosophila models.","method":"Human PD brain analysis (Western blot), A53T αSyn mouse model, iPSC-derived neuron overexpression, mitochondrial function assays, oxidative stress assays, proximity/co-localization assays for αSyn-mitochondria interaction, Drosophila depletion model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple model systems, gain- and loss-of-function, functional mitochondrial readouts; preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.06.13.659577"],"is_preprint":true}],"current_model":"STOML2 is a mitochondrial inner membrane scaffold protein that (1) stabilizes prohibitins and respiratory chain complex subunits, (2) negatively regulates the mitochondrial Na+/Ca2+ exchanger to control mitochondrial Ca2+ homeostasis, (3) is required for stress-induced mitochondrial hyperfusion (SIMH) by maintaining L-OPA1 levels in concert with MFN1, (4) physically interacts with Parkin (via the Parkin RING0 domain) and PINK1 to modulate PINK1-Parkin-dependent mitophagy, (5) is transcriptionally induced by HIF-1α under hypoxia to activate PINK1-dependent mitophagy via PGAM5 cleavage, and (6) interacts with PHB to activate MAPK/ERK signaling in cancer and stem cell contexts, collectively establishing STOML2 as a central regulator of mitochondrial dynamics, quality control, and calcium and energy metabolism."},"narrative":{"teleology":[{"year":2000,"claim":"Establishing STOML2 as a novel stomatin-family member resolved its molecular identity and distinguished it from stomatin by its lack of a transmembrane domain and its peripheral membrane association via the erythrocyte cytoskeleton.","evidence":"cDNA cloning, subcellular fractionation (Triton X-100/NaOH extraction), and COS cell expression","pmids":["10713127"],"confidence":"Medium","gaps":["Mitochondrial localization not yet recognized","Mechanism of membrane association unclear without a hydrophobic anchor","Function beyond structural scaffold uncharacterized"]},{"year":2008,"claim":"Demonstrating that STOML2 resides at the mitochondrial inner membrane and stabilizes prohibitins and respiratory chain complex subunits established its primary organellar context and first mechanistic function as a protein-stability scaffold.","evidence":"Proteomic identification, co-immunoprecipitation of STOML2-PHB, siRNA knockdown showing increased proteolysis of PHB and complexes I/IV subunits in HeLa cells","pmids":["18339324"],"confidence":"High","gaps":["Whether STOML2 directly inhibits a protease or acts via prohibitin ring assembly is unknown","No structural data on the STOML2-PHB interface"]},{"year":2009,"claim":"Identifying STOML2 as essential for stress-induced mitochondrial hyperfusion (SIMH) and for maintaining L-OPA1 levels revealed its role in adaptive mitochondrial dynamics, placing it in a genetic pathway with MFN1 and OPA1 but independent of prohibitins.","evidence":"siRNA epistasis analysis with OPA1/MFN1/MFN2/BAX/BAK/PHB knockdowns, live-cell imaging of mitochondrial morphology, ATP measurement under UV/actinomycin D stress","pmids":["19360003"],"confidence":"High","gaps":["How STOML2 prevents L-OPA1 processing is not determined","Whether STOML2 directly contacts OPA1 or acts through an intermediate protease is unresolved"]},{"year":2009,"claim":"Showing that STOML2 negatively regulates the mitochondrial Na⁺/Ca²⁺ exchanger (mNCX) established a distinct ion-homeostasis function, with STOML2 depletion accelerating Ca²⁺ extrusion and STOML2 overexpression prolonging mitochondrial Ca²⁺ retention.","evidence":"Gain- and loss-of-function Ca²⁺ imaging in permeabilized cells, pharmacological dissection with CGP-37157 and Na⁺ removal","pmids":["19944461"],"confidence":"High","gaps":["Whether STOML2 directly binds the exchanger was not shown until later work","The stoichiometry and membrane topology of the STOML2-mNCX complex are unknown"]},{"year":2013,"claim":"Conservation of STOML2 function in C. elegans, where the ortholog STL-1 is induced by the stress-responsive factor SKN-1/Nrf and promotes mitochondrial fusion during reoxygenation, extended the stress-adaptive role across species and linked STOML2 to oxidative stress transcriptional programs.","evidence":"Genetic epistasis in C. elegans (egl-9, hif-1, skn-1, stl-1 mutants), GFP reporter assays, live mitochondrial imaging","pmids":["24385935"],"confidence":"Medium","gaps":["Ortholog inference; direct mammalian Nrf2-STOML2 regulation not demonstrated","Molecular mechanism of fusion promotion in worms not defined"]},{"year":2017,"claim":"Demonstrating that STOML2 physically interacts with Parkin at mitochondria and that STOML2 overexpression rescues Parkin-deficiency phenotypes in neurons and Drosophila established STOML2 as a functional partner in the Parkin-dependent mitochondrial quality-control pathway.","evidence":"Endogenous co-immunoprecipitation and proximity ligation assay, genetic rescue in iPSC-derived neurons and Drosophila, complex I activity measurement","pmids":["28379402"],"confidence":"High","gaps":["The Parkin binding domain on STOML2 was not mapped","Whether STOML2 modulates Parkin's E3 ubiquitin ligase activity is unknown"]},{"year":2021,"claim":"Two parallel studies revealed that STOML2 interacts with PINK1 to amplify PINK1-Parkin mitophagy under HIF-1α-driven transcriptional induction, and that STOML2 activates MAPK/ERK signaling through PHB in colorectal cancer, broadening its role from mitochondrial scaffold to signaling modulator.","evidence":"STOML2-PINK1 co-immunoprecipitation, ChIP and luciferase reporter for HIF-1α regulation; yeast two-hybrid, co-immunoprecipitation and phospho-ERK Western blots for STOML2-PHB-MAPK axis; orthotopic tumor model","pmids":["33446239","34781982"],"confidence":"High","gaps":["Whether PHB-ERK signaling depends on STOML2's mitochondrial localization or a distinct pool is unclear","The structural basis of STOML2-PINK1 interaction is not defined"]},{"year":2023,"claim":"Identifying STOML2 as a stabilizer of the rhomboid protease PARL, which degrades PINK1, provided a mechanistic link between STOML2 and PINK1 accumulation: STOML2 restrains PINK1-dependent mitophagy by preserving PARL activity under basal conditions.","evidence":"Co-immunoprecipitation of STOML2-PARL, PINK1 protein level changes upon STOML2 manipulation, xenograft chemosensitivity model in pancreatic cancer","pmids":["36906621"],"confidence":"Medium","gaps":["Apparent contradiction with the 2021 finding that STOML2 amplifies PINK1-Parkin mitophagy; context-dependent regulation not reconciled","PARL enzymatic activity not measured directly","Single lab, awaits independent replication"]},{"year":2024,"claim":"Mapping the Parkin-STOML2 interface to the Parkin RING0 domain, and showing that PD-associated PRKN mutations at this interface disrupt binding and that RING0 delivery rescues mitochondrial function, provided the first structural-level insight into the interaction and a potential therapeutic strategy.","evidence":"Domain truncation mapping, proximity ligation assay quantification, computational modeling from crystal structure, high-resolution respirometry in iPSC-derived neurons","pmids":["38229174"],"confidence":"High","gaps":["No co-crystal structure of STOML2-Parkin","Whether the RING0 mini-peptide acts solely through STOML2 or engages other partners is untested"]},{"year":2024,"claim":"Discovery that STOML2 binds TRADD and activates NF-κB signaling to upregulate CCND1, VEGF, and PD-L1 expanded STOML2's signaling repertoire beyond MAPK into inflammatory and immune-evasion pathways in colorectal cancer.","evidence":"Co-immunoprecipitation of STOML2-TRADD, siRNA/overexpression, Western blot, in vivo tumor models","pmids":["38214751"],"confidence":"Medium","gaps":["Whether STOML2-TRADD interaction occurs at mitochondria or another compartment is not defined","Awaits independent replication","Mechanism by which a mitochondrial scaffold engages cytoplasmic TRADD unclear"]},{"year":2025,"claim":"Demonstrating that HIF-1α-induced STOML2 translocates to the outer mitochondrial membrane under hypoxia and promotes PGAM5 cleavage to initiate PINK1-dependent mitophagy refined the mechanistic pathway linking hypoxia sensing to mitophagy execution.","evidence":"Triple knockdown of HIF-1α/STOML2/PGAM5, immunofluorescence for OMM localization, mitophagy and neuronal injury assays, in vivo mouse model","pmids":["41723145"],"confidence":"Medium","gaps":["Mechanism of STOML2 translocation from IMM to OMM unknown","PGAM5 cleavage protease not identified","Single lab study"]},{"year":2026,"claim":"Confirming a direct STOML2-NCLX interaction and linking STOML2 loss to impaired oxidative phosphorylation, elevated ROS, chondrocyte senescence, and ferroptosis extended the calcium-homeostasis function to degenerative disease contexts.","evidence":"Co-immunoprecipitation of STOML2-NCLX, mitochondrial Ca²⁺ and OCR measurement, ROS assay, rat osteoarthritis intra-articular delivery model","pmids":["41995387"],"confidence":"Medium","gaps":["STOML2-NCLX binding interface not mapped","Whether STOML2 regulates NCLX channel gating or membrane stability is unresolved","Single lab"]},{"year":2026,"claim":"Showing that STOML2-PHB sustains ERK signaling and pluripotency factor expression in human pluripotent stem cells generalized the STOML2-PHB-ERK axis beyond cancer to normal stem cell biology.","evidence":"shRNA knockdown, RNA-seq, phospho-ERK Western blot, flow cytometry for pluripotency markers in hPSCs","pmids":["41709508"],"confidence":"Medium","gaps":["Whether STOML2 is required for in vivo embryonic development is untested","PHB ring complex stoichiometry with STOML2 in stem cells unknown"]},{"year":null,"claim":"Key unresolved questions include: (1) the structural basis of STOML2 interactions with PHB, PINK1, PARL, and NCLX; (2) how STOML2 reconciles apparently opposing roles in promoting versus restraining PINK1-dependent mitophagy in different contexts; (3) the mechanism by which STOML2 translocates from the inner to outer mitochondrial membrane under hypoxia; and (4) whether STOML2 plays a non-redundant role in neurodegeneration in vivo.","evidence":"Gaps identified across the literature","pmids":[],"confidence":"High","gaps":["No co-crystal or cryo-EM structure for any STOML2 complex","Context-dependent mitophagy regulation (PARL-mediated restraint vs. PINK1 amplification) not mechanistically reconciled","In vivo mammalian knockout phenotype not reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,6,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,13]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,2,3,4,6,7,9,12,13]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,7,9,12]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,2,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,10,14]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,3,4,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,12]}],"complexes":["PHB1/PHB2 prohibitin complex"],"partners":["PHB","PHB2","PRKN","PINK1","PARL","NCLX","TRADD","OPA1"],"other_free_text":[]},"mechanistic_narrative":"STOML2 is a mitochondrial inner membrane scaffold protein that integrates mitochondrial dynamics, quality control, calcium homeostasis, and respiratory chain maintenance. It physically interacts with prohibitins (PHB1/PHB2) to stabilize respiratory chain complex I and IV subunits, maintains long-form OPA1 (L-OPA1) levels required for stress-induced mitochondrial hyperfusion (SIMH) together with MFN1, and negatively regulates the mitochondrial Na⁺/Ca²⁺ exchanger (NCLX) to control mitochondrial calcium retention [PMID:18339324, PMID:19360003, PMID:19944461, PMID:41995387]. STOML2 modulates PINK1-Parkin-dependent mitophagy through direct interactions with both Parkin (via the RING0 domain) and PINK1, and by stabilizing the rhomboid protease PARL, which controls PINK1 turnover; HIF-1α transcriptionally upregulates STOML2 under hypoxia to activate this mitophagy axis via PGAM5 cleavage [PMID:28379402, PMID:38229174, PMID:33446239, PMID:36906621, PMID:41723145]. Through its interaction with PHB, STOML2 also activates the RAF1-MEK-ERK signaling cascade, a function implicated in both colorectal cancer proliferation and maintenance of pluripotency in human stem cells [PMID:34781982, PMID:41709508]."},"prefetch_data":{"uniprot":{"accession":"Q9UJZ1","full_name":"Stomatin-like protein 2, mitochondrial","aliases":["EPB72-like protein 2","Paraprotein target 7","Paratarg-7"],"length_aa":356,"mass_kda":38.5,"function":"Mitochondrial protein that probably regulates the biogenesis and the activity of mitochondria. Stimulates cardiolipin biosynthesis, binds cardiolipin-enriched membranes where it recruits and stabilizes some proteins including prohibitin and may therefore act in the organization of functional microdomains in mitochondrial membranes. Through regulation of the mitochondrial function may play a role into several biological processes including cell migration, cell proliferation, T-cell activation, calcium homeostasis and cellular response to stress. May play a role in calcium homeostasis through negative regulation of calcium efflux from mitochondria. Required for mitochondrial hyperfusion a pro-survival cellular response to stress which results in increased ATP production by mitochondria. May also regulate the organization of functional domains at the plasma membrane and play a role in T-cell activation through association with the T-cell receptor signaling complex and its regulation","subcellular_location":"Cell membrane; Mitochondrion; Mitochondrion inner membrane; Mitochondrion intermembrane space; Membrane raft; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q9UJZ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STOML2","classification":"Not Classified","n_dependent_lines":39,"n_total_lines":1208,"dependency_fraction":0.03228476821192053},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/STOML2","total_profiled":1310},"omim":[{"mim_id":"615121","title":"STOMATIN-LIKE PROTEIN-2, HYPERPHOSPHORYLATION OF","url":"https://www.omim.org/entry/615121"},{"mim_id":"615088","title":"AUTOPHAGY-RELATED 13; ATG13","url":"https://www.omim.org/entry/615088"},{"mim_id":"610704","title":"PROHIBITIN 2; PHB2","url":"https://www.omim.org/entry/610704"},{"mim_id":"608292","title":"STOMATIN-LIKE PROTEIN 2; STOML2","url":"https://www.omim.org/entry/608292"},{"mim_id":"254500","title":"MYELOMA, MULTIPLE","url":"https://www.omim.org/entry/254500"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STOML2"},"hgnc":{"alias_symbol":["SLP-2","HSPC108"],"prev_symbol":[]},"alphafold":{"accession":"Q9UJZ1","domains":[{"cath_id":"-","chopping":"33-79","consensus_level":"medium","plddt":89.7849,"start":33,"end":79},{"cath_id":"3.30.479.30","chopping":"81-182","consensus_level":"medium","plddt":94.3377,"start":81,"end":182},{"cath_id":"1.20.5","chopping":"207-265","consensus_level":"medium","plddt":93.6673,"start":207,"end":265}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJZ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJZ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJZ1-F1-predicted_aligned_error_v6.png","plddt_mean":80.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STOML2","jax_strain_url":"https://www.jax.org/strain/search?query=STOML2"},"sequence":{"accession":"Q9UJZ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UJZ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UJZ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJZ1"}},"corpus_meta":[{"pmid":"19360003","id":"PMC_19360003","title":"SLP-2 is required for stress-induced mitochondrial hyperfusion.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19360003","citation_count":628,"is_preprint":false},{"pmid":"33446239","id":"PMC_33446239","title":"STOML2 potentiates metastasis of hepatocellular carcinoma by promoting PINK1-mediated mitophagy and regulates sensitivity to lenvatinib.","date":"2021","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33446239","citation_count":135,"is_preprint":false},{"pmid":"10713127","id":"PMC_10713127","title":"Identification and characterization of human SLP-2, a novel homologue of stomatin (band 7.2b) present in erythrocytes and other tissues.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10713127","citation_count":99,"is_preprint":false},{"pmid":"18339324","id":"PMC_18339324","title":"SLP-2 interacts with prohibitins in the mitochondrial inner membrane and contributes to their stability.","date":"2008","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/18339324","citation_count":74,"is_preprint":false},{"pmid":"28379402","id":"PMC_28379402","title":"SLP-2 interacts with Parkin in mitochondria and prevents mitochondrial dysfunction in Parkin-deficient human iPSC-derived neurons and Drosophila.","date":"2017","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28379402","citation_count":49,"is_preprint":false},{"pmid":"24385935","id":"PMC_24385935","title":"Anoxia-reoxygenation regulates mitochondrial dynamics through the hypoxia response pathway, SKN-1/Nrf, and stomatin-like protein STL-1/SLP-2.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24385935","citation_count":48,"is_preprint":false},{"pmid":"19597348","id":"PMC_19597348","title":"Downregulation of a mitochondria associated protein SLP-2 inhibits tumor cell motility, proliferation and enhances cell sensitivity to chemotherapeutic reagents.","date":"2009","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/19597348","citation_count":40,"is_preprint":false},{"pmid":"36906621","id":"PMC_36906621","title":"STOML2 restricts mitophagy and increases chemosensitivity in pancreatic cancer through stabilizing PARL-induced PINK1 degradation.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36906621","citation_count":39,"is_preprint":false},{"pmid":"21960069","id":"PMC_21960069","title":"Knockdown of stomatin-like protein 2 (STOML2) reduces the invasive ability of glioma cells through inhibition of the NF-κB/MMP-9 pathway.","date":"2011","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21960069","citation_count":30,"is_preprint":false},{"pmid":"19944461","id":"PMC_19944461","title":"SLP-2 negatively modulates mitochondrial sodium-calcium exchange.","date":"2009","source":"Cell 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Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/29951933","citation_count":19,"is_preprint":false},{"pmid":"35851063","id":"PMC_35851063","title":"Cytochrome B5 type A alleviates HCC metastasis via regulating STOML2 related autophagy and promoting sensitivity to ruxolitinib.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35851063","citation_count":18,"is_preprint":false},{"pmid":"34781982","id":"PMC_34781982","title":"STOML2 interacts with PHB through activating MAPK signaling pathway to promote colorectal Cancer proliferation.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/34781982","citation_count":17,"is_preprint":false},{"pmid":"23667687","id":"PMC_23667687","title":"Expression of SLP-2 was associated with invasion of esophageal squamous cell carcinoma.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23667687","citation_count":17,"is_preprint":false},{"pmid":"23918306","id":"PMC_23918306","title":"Clinicopathological significance of SLP-2 overexpression in human gallbladder cancer.","date":"2013","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23918306","citation_count":12,"is_preprint":false},{"pmid":"24258357","id":"PMC_24258357","title":"Increased expression of stomatin-like protein 2 (STOML2) predicts decreased survival in gastric adenocarcinoma: a retrospective study.","date":"2013","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/24258357","citation_count":11,"is_preprint":false},{"pmid":"30944651","id":"PMC_30944651","title":"Expression and clinical significance of SLP-2 in ovarian tumors.","date":"2019","source":"Oncology 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structure.","date":"2006","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/16671055","citation_count":8,"is_preprint":false},{"pmid":"32141532","id":"PMC_32141532","title":"Clinical significance of SLP-2 in epithelial ovarian cancer and its regulatory effect on the Notch signaling pathway.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32141532","citation_count":8,"is_preprint":false},{"pmid":"38214751","id":"PMC_38214751","title":"Overexpressing lipid raft protein STOML2 modulates the tumor microenvironment via NF-κB signaling in colorectal cancer.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/38214751","citation_count":7,"is_preprint":false},{"pmid":"26932604","id":"PMC_26932604","title":"Identification of STOML2 as a putative novel asthma risk gene associated with IL6R.","date":"2016","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/26932604","citation_count":7,"is_preprint":false},{"pmid":"32402568","id":"PMC_32402568","title":"Coexisting overexpression of STOML1 and STOML2 proteins may be associated with pathology of oral squamous cell carcinoma.","date":"2020","source":"Oral surgery, oral medicine, oral pathology and oral radiology","url":"https://pubmed.ncbi.nlm.nih.gov/32402568","citation_count":7,"is_preprint":false},{"pmid":"29033585","id":"PMC_29033585","title":"Clinical significance of SLP-2 in hepatocellular carcinoma tissues and its regulation in cancer cell proliferation, migration, and EMT.","date":"2017","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29033585","citation_count":7,"is_preprint":false},{"pmid":"34457062","id":"PMC_34457062","title":"Effect and mechanism of action of SLP-2 on the apoptosis and autophagy of gastric cancer cells.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/34457062","citation_count":5,"is_preprint":false},{"pmid":"34774067","id":"PMC_34774067","title":"Expression of STOML2 promotes proliferation and glycolysis of multiple myeloma cells via upregulating PAI-1.","date":"2021","source":"Journal of orthopaedic surgery and research","url":"https://pubmed.ncbi.nlm.nih.gov/34774067","citation_count":4,"is_preprint":false},{"pmid":"40371153","id":"PMC_40371153","title":"STOML2 inhibits sorafenib-induced ferroptosis in hepatocellular carcinoma via p-AKT signaling pathway.","date":"2025","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/40371153","citation_count":4,"is_preprint":false},{"pmid":"36527788","id":"PMC_36527788","title":"SLP-2 regulates the generation of reactive oxygen species and the ERK pathway to promote papillary thyroid carcinoma motility and angiogenesis.","date":"2022","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/36527788","citation_count":4,"is_preprint":false},{"pmid":"38229174","id":"PMC_38229174","title":"Intracellular delivery of Parkin-RING0-based fragments corrects Parkin-induced mitochondrial dysfunction through interaction with SLP-2.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38229174","citation_count":2,"is_preprint":false},{"pmid":"16202296","id":"PMC_16202296","title":"[Expression of SLP-2 mRNA in endometrial cancer and its significance].","date":"2005","source":"Zhonghua fu chan ke za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/16202296","citation_count":2,"is_preprint":false},{"pmid":"41347828","id":"PMC_41347828","title":"STOML2 interacts with PHB to activate the MEK/ERK signaling pathway and mediates autophagy‑related proteins in the progression of hepatocellular carcinoma.","date":"2025","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41347828","citation_count":1,"is_preprint":false},{"pmid":"40787720","id":"PMC_40787720","title":"STOML2 knockdown inhibits inflammation and airway remodeling of PDGF-BB-induced airway smooth-muscle cells by the MAPK pathway.","date":"2025","source":"The Journal of asthma : official journal of the Association for the Care of Asthma","url":"https://pubmed.ncbi.nlm.nih.gov/40787720","citation_count":1,"is_preprint":false},{"pmid":"26403741","id":"PMC_26403741","title":"[Overexpression of STOML-2 inhibits apoptosis of human cervical squamous carcinoma Siha cells in vitro].","date":"2015","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/26403741","citation_count":1,"is_preprint":false},{"pmid":"41709508","id":"PMC_41709508","title":"STOML2 Maintains Pluripotency and Cell Cycle Integrity in Human Pluripotent Stem Cells via PHB-ERK Signaling.","date":"2026","source":"International journal of stem cells","url":"https://pubmed.ncbi.nlm.nih.gov/41709508","citation_count":0,"is_preprint":false},{"pmid":"41619509","id":"PMC_41619509","title":"STOML2 is not essential for spermatogenesis and male fertility in mice.","date":"2026","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41619509","citation_count":0,"is_preprint":false},{"pmid":"41995387","id":"PMC_41995387","title":"STOML2 Alleviates Osteoarthritis by Regulating Mitochondrial Energy Metabolism and Oxidative Stress.","date":"2026","source":"Genetics research","url":"https://pubmed.ncbi.nlm.nih.gov/41995387","citation_count":0,"is_preprint":false},{"pmid":"41743019","id":"PMC_41743019","title":"STOML2 promotes hepatocellular carcinoma cell proliferation, invasion and migration by activating the PI3K/AKT signaling pathway (Review).","date":"2026","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/41743019","citation_count":0,"is_preprint":false},{"pmid":"33168500","id":"PMC_33168500","title":"[Silencing of SLP-2 inhibits the migration and invasion of cervical cancer cells in vitro].","date":"2018","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/33168500","citation_count":0,"is_preprint":false},{"pmid":"41723145","id":"PMC_41723145","title":"Novel mechanism of neuronal hypoxia response: HIF-1α/STOML2 mediated PINK1-dependent mitophagy activation against neuronal injury.","date":"2026","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41723145","citation_count":0,"is_preprint":false},{"pmid":"21223688","id":"PMC_21223688","title":"[Expression of SLP-2 protein in esophageal squamous cell carcinoma is associated with cancer invasion].","date":"2010","source":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","url":"https://pubmed.ncbi.nlm.nih.gov/21223688","citation_count":0,"is_preprint":false},{"pmid":"36003327","id":"PMC_36003327","title":"Clinical Significance of SLP-2 in Hepatocellular Carcinoma Tissues and Its Regulation in Cancer Cell Proliferation, Migration, and EMT [Retraction].","date":"2022","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/36003327","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.16.649120","title":"HIF-1α/STOML2 mediated PINK1-dependent mitophagy activation against hypoxia-induced neuronal injury","date":"2025-04-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.16.649120","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.04.657971","title":"Preliminary insights into salivary proteomic versus targeted biomarker profiles associated with acute physical fatigue","date":"2025-06-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.04.657971","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.13.659577","title":"Modulation of SLP-2 expression protects against alpha-synuclein neuropathology by mitigating mitochondrial dysfunction","date":"2025-06-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.13.659577","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24848,"output_tokens":4358,"usd":0.069957},"stage2":{"model":"claude-opus-4-6","input_tokens":7807,"output_tokens":3792,"usd":0.200753},"total_usd":0.27071,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"SLP-2 (STOML2) was cloned and characterized as a novel stomatin homologue present in erythrocytes and other tissues. It partitions into both Triton X-100-soluble and -insoluble pools, is fully extractable by NaOH (unlike stomatin, indicating no direct membrane bilayer insertion), and interacts with the peripheral erythrocyte cytoskeleton. It lacks the N-terminal hydrophobic domain found in other stomatin family members.\",\n      \"method\": \"cDNA cloning, Northern/Western blot, subcellular fractionation (Triton X-100, NaOH extraction), SDS-PAGE, expression in COS cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical fractionation and localization experiments, single lab, moderate orthogonal methods\",\n      \"pmids\": [\"10713127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SLP-2 is strongly associated with the mitochondrial inner membrane and physically interacts with prohibitins (PHB1/PHB2). Depletion of SLP-2 in HeLa cells leads to increased proteolysis of prohibitins and subunits of respiratory chain complexes I and IV, indicating SLP-2 regulates the stability of these mitochondrial proteins.\",\n      \"method\": \"Proteomic approaches, co-immunoprecipitation, siRNA knockdown, subcellular fractionation, Western blot\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction demonstrated, loss-of-function with specific molecular phenotype (proteolysis of defined substrates), replicated proteomic identification\",\n      \"pmids\": [\"18339324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SLP-2 is required for stress-induced mitochondrial hyperfusion (SIMH). In the absence of SLP-2, long-form OPA1 (L-OPA1) is lost and SIMH is prevented. SIMH requires L-OPA1, MFN1, and SLP-2 but is independent of MFN2, BAX/BAK, and prohibitins. SIMH is accompanied by increased mitochondrial ATP production and represents a pro-survival adaptive response.\",\n      \"method\": \"siRNA knockdown, live-cell imaging of mitochondrial morphology, epistasis analysis (double knockdown/knockout), ATP measurement, UV/actinomycin D stress models\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple defined components, clean KO/KD with specific morphological and biochemical phenotypes, highly cited foundational study\",\n      \"pmids\": [\"19360003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SLP-2 modulates mitochondrial sodium-calcium exchange. SLP-2 depletion increases rates of Ca2+ extrusion from mitochondria via the mitochondrial Na+/Ca2+ exchanger (mNCX); this effect is abolished by Na+ removal or CGP-37157 (mNCX inhibitor). SLP-2 overexpression prolongs mitochondrial Ca2+ retention, and SLP-2 depletion increases cytosolic Ca2+ elevations, demonstrating SLP-2 negatively regulates mNCX activity.\",\n      \"method\": \"siRNA knockdown, SLP-2 overexpression, mitochondrial and cytosolic Ca2+ imaging, pharmacological inhibition (CGP-37157, Na+ removal), permeabilized cell assays\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — gain- and loss-of-function with pharmacological dissection of specific transporter, mechanistic specificity confirmed by Na+ removal and inhibitor experiments\",\n      \"pmids\": [\"19944461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SLP-2 localizes to mitochondria, maintains mitochondrial membrane potential (MMP) and ATP production, and its knockdown inhibits cell motility and proliferation and enhances chemosensitivity in tumor cells.\",\n      \"method\": \"siRNA knockdown, immunofluorescence (mitochondrial localization), MMP assay, ATP measurement, cell motility assays, cell proliferation assays\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — localization confirmed, functional consequences measured, single lab\",\n      \"pmids\": [\"19597348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In C. elegans, the STOML2 ortholog STL-1 (Stomatin-like 1) is transcriptionally induced by SKN-1/Nrf in response to anoxia and facilitates mitochondrial fusion dynamics during reoxygenation. This places STOML2 downstream of the oxidative stress response factor SKN-1 in controlling mitochondrial fission/fusion balance.\",\n      \"method\": \"Genetic epistasis in C. elegans, live imaging of mitochondrial morphology, GFP reporter assays, mutant analysis (egl-9, hif-1, skn-1, stl-1)\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in C. elegans ortholog, multiple mutant combinations, functional mitochondrial imaging; ortholog inference\",\n      \"pmids\": [\"24385935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SLP-2 physically interacts with Parkin at mitochondria. Co-immunoprecipitation and proximity ligation assays demonstrated endogenous interaction. SLP-2 and Parkin genetically interact: SLP-2 overexpression rescues Parkin-deficiency phenotypes (reduced complex I activity, abnormal mitochondrial morphology, loss of dopaminergic neurons, reduced ATP, motor dysfunction) in iPSC-derived neurons and Drosophila. SLP-2 is placed epistatic to Parkin in maintaining mitochondrial respiratory chain function.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay (endogenous proteins), siRNA knockdown, iPSC-derived neuron models, Drosophila genetic rescue experiments, respiratory chain complex I activity assay, mitochondrial network imaging\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction by two orthogonal methods, genetic epistasis in two independent model systems (neurons and Drosophila), multiple functional readouts\",\n      \"pmids\": [\"28379402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STOML2 interacts with and stabilizes PINK1 under cellular stress conditions, amplifying PINK1-Parkin-mediated mitophagy. HIF-1α transcriptionally upregulates STOML2 expression. The STOML2-PINK1 interaction was demonstrated by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation, laser confocal microscopy, flow cytometry, transmission electron microscopy, Western blot, ChIP assay, luciferase reporter assay\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein-protein interaction by Co-IP, transcriptional regulation confirmed by ChIP and luciferase reporter, multiple orthogonal methods\",\n      \"pmids\": [\"33446239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STOML2 interacts with prohibitin (PHB) and activates the MAPK signaling pathway (RAF1, MEK1/2, ERK1/2 phosphorylation) to promote colorectal cancer proliferation. The STOML2-PHB interaction was confirmed by co-immunoprecipitation and immunofluorescence co-localization. Knockdown of STOML2 downregulates MAPK pathway phosphorylation.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, immunofluorescence, Western blot (phospho-RAF1/MEK/ERK), siRNA knockdown, organoid culture, orthotopic tumor model\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — interaction validated by Co-IP and co-localization, pathway effect shown by Western blot, single lab\",\n      \"pmids\": [\"34781982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STOML2 stabilizes PARL (presenilin-associated rhomboid-like protease) at the mitochondrial inner membrane, preventing PARL-mediated PINK1 degradation and thereby restricting PINK1-dependent mitophagy. In pancreatic cancer, this STOML2-PARL-PINK1 axis controls mitochondrial mass and chemosensitivity.\",\n      \"method\": \"Tissue microarray, siRNA/overexpression, Western blot, co-immunoprecipitation (STOML2-PARL interaction), flow cytometry, mitochondrial mass measurement, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP demonstrating STOML2-PARL interaction, functional consequences on PINK1 degradation measured, single lab\",\n      \"pmids\": [\"36906621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STOML2 physically binds TRADD protein and activates NF-κB signaling, resulting in upregulation of CCND1, VEGF, and PD-L1 in colorectal cancer, thereby promoting proliferation, angiogenesis, and immune escape.\",\n      \"method\": \"Co-immunoprecipitation (STOML2-TRADD binding), siRNA/overexpression, Western blot, in vitro and in vivo tumor models\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP for interaction, functional pathway readouts, single lab\",\n      \"pmids\": [\"38214751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The Parkin-SLP-2 interaction is mediated primarily through the Parkin RING0 domain. PD-associated PRKN missense mutations that overlap with SLP-2 binding sites reduce the Parkin-SLP-2 interaction. Delivery of the isolated Parkin RING0 domain or a derived mini-peptide rescues mitochondrial dysfunction in Parkin-deficient neuroblastoma cells and iPSC-derived neurons.\",\n      \"method\": \"Proximity ligation assay (quantitative), domain mapping (truncation constructs), computational structural modeling (crystal structure-based), high-resolution respirometry, immunofluorescence, live imaging, iPSC-derived neurons\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structural prediction validated by domain mapping and functional rescue, interaction quantified in disease-relevant neurons, multiple orthogonal methods\",\n      \"pmids\": [\"38229174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under hypoxia, HIF-1α transcriptionally induces STOML2 expression. STOML2 then translocates to the outer mitochondrial membrane and participates in PGAM5 cleavage, initiating PINK1-dependent mitophagy as a neuroprotective response. Knockdown of HIF-1α, STOML2, or PGAM5 inhibits this mitophagy and worsens neuronal injury.\",\n      \"method\": \"siRNA knockdown of HIF-1α/STOML2/PGAM5, overexpression, immunofluorescence (mitochondrial localization), mitophagy assays, neuronal injury assays, in vivo mouse model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistatic pathway dissected by triple knockdown, localization confirmed; single lab, peer-reviewed\",\n      \"pmids\": [\"41723145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STOML2 interacts with the mitochondrial Na+/Ca2+ exchanger NCLX to support mitochondrial Ca2+ efflux and metabolic stability. STOML2 depletion impairs oxidative phosphorylation, elevates mitochondrial ROS, and promotes chondrocyte senescence and ferroptotic cell death in osteoarthritis models.\",\n      \"method\": \"Co-immunoprecipitation (STOML2-NCLX), siRNA knockdown, STOML2 overexpression, mitochondrial Ca2+ measurement, OCR measurement, ROS assay, intra-articular delivery in rat OA model\",\n      \"journal\": \"Genetics research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — STOML2-NCLX interaction by Co-IP, functional Ca2+ measurements, in vivo validation; single lab\",\n      \"pmids\": [\"41995387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STOML2 and PHB form a functional axis that maintains ERK/MAPK signaling activity and pluripotency in human pluripotent stem cells. STOML2 knockdown reduces OCT4, NANOG, PHB, and phosphorylated ERK while increasing differentiation markers, demonstrating STOML2 is required for hPSC self-renewal through the PHB-ERK pathway.\",\n      \"method\": \"shRNA knockdown, transcriptomic profiling (RNA-seq), Western blot (phospho-ERK), immunofluorescence, flow cytometry\",\n      \"journal\": \"International journal of stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss-of-function with specific pluripotency and signaling phenotypes, pathway confirmed by phospho-protein measurement; single lab\",\n      \"pmids\": [\"41709508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLP-2 overexpression protects against alpha-synuclein-induced mitochondrial dysfunction and dopaminergic neuron loss. SLP-2 levels are reduced in human PD brains and in an A53T alpha-synuclein mouse model. SLP-2 overexpression in iPSC-derived neurons improves mitochondrial function, reduces oxidative stress, and prevents alpha-synuclein-mitochondria interactions. SLP-2 depletion exacerbates degeneration in mouse and Drosophila models.\",\n      \"method\": \"Human PD brain analysis (Western blot), A53T αSyn mouse model, iPSC-derived neuron overexpression, mitochondrial function assays, oxidative stress assays, proximity/co-localization assays for αSyn-mitochondria interaction, Drosophila depletion model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple model systems, gain- and loss-of-function, functional mitochondrial readouts; preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.06.13.659577\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"STOML2 is a mitochondrial inner membrane scaffold protein that (1) stabilizes prohibitins and respiratory chain complex subunits, (2) negatively regulates the mitochondrial Na+/Ca2+ exchanger to control mitochondrial Ca2+ homeostasis, (3) is required for stress-induced mitochondrial hyperfusion (SIMH) by maintaining L-OPA1 levels in concert with MFN1, (4) physically interacts with Parkin (via the Parkin RING0 domain) and PINK1 to modulate PINK1-Parkin-dependent mitophagy, (5) is transcriptionally induced by HIF-1α under hypoxia to activate PINK1-dependent mitophagy via PGAM5 cleavage, and (6) interacts with PHB to activate MAPK/ERK signaling in cancer and stem cell contexts, collectively establishing STOML2 as a central regulator of mitochondrial dynamics, quality control, and calcium and energy metabolism.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"STOML2 is a mitochondrial inner membrane scaffold protein that integrates mitochondrial dynamics, quality control, calcium homeostasis, and respiratory chain maintenance. It physically interacts with prohibitins (PHB1/PHB2) to stabilize respiratory chain complex I and IV subunits, maintains long-form OPA1 (L-OPA1) levels required for stress-induced mitochondrial hyperfusion (SIMH) together with MFN1, and negatively regulates the mitochondrial Na⁺/Ca²⁺ exchanger (NCLX) to control mitochondrial calcium retention [PMID:18339324, PMID:19360003, PMID:19944461, PMID:41995387]. STOML2 modulates PINK1-Parkin-dependent mitophagy through direct interactions with both Parkin (via the RING0 domain) and PINK1, and by stabilizing the rhomboid protease PARL, which controls PINK1 turnover; HIF-1α transcriptionally upregulates STOML2 under hypoxia to activate this mitophagy axis via PGAM5 cleavage [PMID:28379402, PMID:38229174, PMID:33446239, PMID:36906621, PMID:41723145]. Through its interaction with PHB, STOML2 also activates the RAF1-MEK-ERK signaling cascade, a function implicated in both colorectal cancer proliferation and maintenance of pluripotency in human stem cells [PMID:34781982, PMID:41709508].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing STOML2 as a novel stomatin-family member resolved its molecular identity and distinguished it from stomatin by its lack of a transmembrane domain and its peripheral membrane association via the erythrocyte cytoskeleton.\",\n      \"evidence\": \"cDNA cloning, subcellular fractionation (Triton X-100/NaOH extraction), and COS cell expression\",\n      \"pmids\": [\"10713127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial localization not yet recognized\", \"Mechanism of membrane association unclear without a hydrophobic anchor\", \"Function beyond structural scaffold uncharacterized\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that STOML2 resides at the mitochondrial inner membrane and stabilizes prohibitins and respiratory chain complex subunits established its primary organellar context and first mechanistic function as a protein-stability scaffold.\",\n      \"evidence\": \"Proteomic identification, co-immunoprecipitation of STOML2-PHB, siRNA knockdown showing increased proteolysis of PHB and complexes I/IV subunits in HeLa cells\",\n      \"pmids\": [\"18339324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STOML2 directly inhibits a protease or acts via prohibitin ring assembly is unknown\", \"No structural data on the STOML2-PHB interface\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying STOML2 as essential for stress-induced mitochondrial hyperfusion (SIMH) and for maintaining L-OPA1 levels revealed its role in adaptive mitochondrial dynamics, placing it in a genetic pathway with MFN1 and OPA1 but independent of prohibitins.\",\n      \"evidence\": \"siRNA epistasis analysis with OPA1/MFN1/MFN2/BAX/BAK/PHB knockdowns, live-cell imaging of mitochondrial morphology, ATP measurement under UV/actinomycin D stress\",\n      \"pmids\": [\"19360003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How STOML2 prevents L-OPA1 processing is not determined\", \"Whether STOML2 directly contacts OPA1 or acts through an intermediate protease is unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showing that STOML2 negatively regulates the mitochondrial Na⁺/Ca²⁺ exchanger (mNCX) established a distinct ion-homeostasis function, with STOML2 depletion accelerating Ca²⁺ extrusion and STOML2 overexpression prolonging mitochondrial Ca²⁺ retention.\",\n      \"evidence\": \"Gain- and loss-of-function Ca²⁺ imaging in permeabilized cells, pharmacological dissection with CGP-37157 and Na⁺ removal\",\n      \"pmids\": [\"19944461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STOML2 directly binds the exchanger was not shown until later work\", \"The stoichiometry and membrane topology of the STOML2-mNCX complex are unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Conservation of STOML2 function in C. elegans, where the ortholog STL-1 is induced by the stress-responsive factor SKN-1/Nrf and promotes mitochondrial fusion during reoxygenation, extended the stress-adaptive role across species and linked STOML2 to oxidative stress transcriptional programs.\",\n      \"evidence\": \"Genetic epistasis in C. elegans (egl-9, hif-1, skn-1, stl-1 mutants), GFP reporter assays, live mitochondrial imaging\",\n      \"pmids\": [\"24385935\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog inference; direct mammalian Nrf2-STOML2 regulation not demonstrated\", \"Molecular mechanism of fusion promotion in worms not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that STOML2 physically interacts with Parkin at mitochondria and that STOML2 overexpression rescues Parkin-deficiency phenotypes in neurons and Drosophila established STOML2 as a functional partner in the Parkin-dependent mitochondrial quality-control pathway.\",\n      \"evidence\": \"Endogenous co-immunoprecipitation and proximity ligation assay, genetic rescue in iPSC-derived neurons and Drosophila, complex I activity measurement\",\n      \"pmids\": [\"28379402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The Parkin binding domain on STOML2 was not mapped\", \"Whether STOML2 modulates Parkin's E3 ubiquitin ligase activity is unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two parallel studies revealed that STOML2 interacts with PINK1 to amplify PINK1-Parkin mitophagy under HIF-1α-driven transcriptional induction, and that STOML2 activates MAPK/ERK signaling through PHB in colorectal cancer, broadening its role from mitochondrial scaffold to signaling modulator.\",\n      \"evidence\": \"STOML2-PINK1 co-immunoprecipitation, ChIP and luciferase reporter for HIF-1α regulation; yeast two-hybrid, co-immunoprecipitation and phospho-ERK Western blots for STOML2-PHB-MAPK axis; orthotopic tumor model\",\n      \"pmids\": [\"33446239\", \"34781982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PHB-ERK signaling depends on STOML2's mitochondrial localization or a distinct pool is unclear\", \"The structural basis of STOML2-PINK1 interaction is not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying STOML2 as a stabilizer of the rhomboid protease PARL, which degrades PINK1, provided a mechanistic link between STOML2 and PINK1 accumulation: STOML2 restrains PINK1-dependent mitophagy by preserving PARL activity under basal conditions.\",\n      \"evidence\": \"Co-immunoprecipitation of STOML2-PARL, PINK1 protein level changes upon STOML2 manipulation, xenograft chemosensitivity model in pancreatic cancer\",\n      \"pmids\": [\"36906621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent contradiction with the 2021 finding that STOML2 amplifies PINK1-Parkin mitophagy; context-dependent regulation not reconciled\", \"PARL enzymatic activity not measured directly\", \"Single lab, awaits independent replication\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapping the Parkin-STOML2 interface to the Parkin RING0 domain, and showing that PD-associated PRKN mutations at this interface disrupt binding and that RING0 delivery rescues mitochondrial function, provided the first structural-level insight into the interaction and a potential therapeutic strategy.\",\n      \"evidence\": \"Domain truncation mapping, proximity ligation assay quantification, computational modeling from crystal structure, high-resolution respirometry in iPSC-derived neurons\",\n      \"pmids\": [\"38229174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure of STOML2-Parkin\", \"Whether the RING0 mini-peptide acts solely through STOML2 or engages other partners is untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that STOML2 binds TRADD and activates NF-κB signaling to upregulate CCND1, VEGF, and PD-L1 expanded STOML2's signaling repertoire beyond MAPK into inflammatory and immune-evasion pathways in colorectal cancer.\",\n      \"evidence\": \"Co-immunoprecipitation of STOML2-TRADD, siRNA/overexpression, Western blot, in vivo tumor models\",\n      \"pmids\": [\"38214751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STOML2-TRADD interaction occurs at mitochondria or another compartment is not defined\", \"Awaits independent replication\", \"Mechanism by which a mitochondrial scaffold engages cytoplasmic TRADD unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that HIF-1α-induced STOML2 translocates to the outer mitochondrial membrane under hypoxia and promotes PGAM5 cleavage to initiate PINK1-dependent mitophagy refined the mechanistic pathway linking hypoxia sensing to mitophagy execution.\",\n      \"evidence\": \"Triple knockdown of HIF-1α/STOML2/PGAM5, immunofluorescence for OMM localization, mitophagy and neuronal injury assays, in vivo mouse model\",\n      \"pmids\": [\"41723145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of STOML2 translocation from IMM to OMM unknown\", \"PGAM5 cleavage protease not identified\", \"Single lab study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirming a direct STOML2-NCLX interaction and linking STOML2 loss to impaired oxidative phosphorylation, elevated ROS, chondrocyte senescence, and ferroptosis extended the calcium-homeostasis function to degenerative disease contexts.\",\n      \"evidence\": \"Co-immunoprecipitation of STOML2-NCLX, mitochondrial Ca²⁺ and OCR measurement, ROS assay, rat osteoarthritis intra-articular delivery model\",\n      \"pmids\": [\"41995387\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"STOML2-NCLX binding interface not mapped\", \"Whether STOML2 regulates NCLX channel gating or membrane stability is unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showing that STOML2-PHB sustains ERK signaling and pluripotency factor expression in human pluripotent stem cells generalized the STOML2-PHB-ERK axis beyond cancer to normal stem cell biology.\",\n      \"evidence\": \"shRNA knockdown, RNA-seq, phospho-ERK Western blot, flow cytometry for pluripotency markers in hPSCs\",\n      \"pmids\": [\"41709508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STOML2 is required for in vivo embryonic development is untested\", \"PHB ring complex stoichiometry with STOML2 in stem cells unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the structural basis of STOML2 interactions with PHB, PINK1, PARL, and NCLX; (2) how STOML2 reconciles apparently opposing roles in promoting versus restraining PINK1-dependent mitophagy in different contexts; (3) the mechanism by which STOML2 translocates from the inner to outer mitochondrial membrane under hypoxia; and (4) whether STOML2 plays a non-redundant role in neurodegeneration in vivo.\",\n      \"evidence\": \"Gaps identified across the literature\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal or cryo-EM structure for any STOML2 complex\", \"Context-dependent mitophagy regulation (PARL-mediated restraint vs. PINK1 amplification) not mechanistically reconciled\", \"In vivo mammalian knockout phenotype not reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 6, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 2, 3, 4, 6, 7, 9, 12, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 7, 9, 12]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 10, 14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 3, 4, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 12]}\n    ],\n    \"complexes\": [\n      \"PHB1/PHB2 prohibitin complex\"\n    ],\n    \"partners\": [\n      \"PHB\",\n      \"PHB2\",\n      \"PRKN\",\n      \"PINK1\",\n      \"PARL\",\n      \"NCLX\",\n      \"TRADD\",\n      \"OPA1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}