{"gene":"STOML2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2000,"finding":"SLP-2 (STOML2) was identified as a novel stomatin homologue present in erythrocytes and other tissues. It lacks the N-terminal hydrophobic domain of other stomatin homologues, is fully extractable from membranes by NaOH (pH 11), and partitions into both Triton X-100-soluble and -insoluble pools. It was shown to interact with the peripheral erythrocyte cytoskeleton but not directly with the membrane bilayer.","method":"Cloning, Western blot, SDS-PAGE, NaOH extraction, Triton X-100 fractionation, expression in COS cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation and membrane extraction with two orthogonal methods in a single founding study","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 of subunits of respiratory chain complexes I and IV, indicating SLP-2 stabilizes these proteins.","method":"Proteomic fractionation, co-immunoprecipitation, SLP-2 siRNA knockdown, Western blot for prohibitin and respiratory chain subunit levels","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal protein interaction confirmed by Co-IP, functional consequence (proteolysis) demonstrated by KD with two orthogonal readouts in a single focused study","pmids":["18339324"],"is_preprint":false},{"year":2009,"finding":"SLP-2 is required for stress-induced mitochondrial hyperfusion (SIMH). In cells exposed to selective stresses (UV irradiation, actinomycin D), mitochondria hyperfuse in an MFN1- and L-OPA1-dependent manner; depletion of SLP-2 abolishes SIMH and causes loss of L-OPA1. SIMH is accompanied by increased mitochondrial ATP production and represents a pro-survival adaptive response.","method":"SLP-2 siRNA knockdown, mitochondrial morphology imaging, immunoblot for OPA1 isoforms, ATP production assay, epistasis with MFN1/MFN2/BAX/BAK/prohibitin knockdowns","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis plus multiple orthogonal phenotypic readouts (morphology, OPA1 processing, ATP), replicated across stress conditions","pmids":["19360003"],"is_preprint":false},{"year":2009,"finding":"SLP-2 localizes to mitochondria, where it affects mitochondrial membrane potential (MMP) and ATP production. Knockdown of SLP-2 by siRNA inhibits cell motility, proliferation, and enhances chemosensitivity, with decreased MMP and ATP levels.","method":"siRNA knockdown, mitochondrial membrane potential assay, ATP production assay, immunofluorescence localization, proliferation and motility assays","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct mitochondrial localization confirmed by immunofluorescence, functional consequence of KD shown by two biochemical readouts (MMP, ATP), single lab","pmids":["19597348"],"is_preprint":false},{"year":2009,"finding":"SLP-2 negatively modulates mitochondrial sodium-calcium exchange (Na+/Ca2+ exchanger). SLP-2 depletion in HeLa cells increased rates of mitochondrial Ca2+ extrusion via the Na+/Ca2+ exchanger, an effect blocked by Na+ removal or CGP-37157 (NCX inhibitor). SLP-2 overexpression prolonged mitochondrial Ca2+ retention and decreased cytosolic Ca2+ elevations.","method":"siRNA knockdown, SLP-2 overexpression, mitochondrial Ca2+ imaging, pharmacological inhibition (CGP-37157, Na+ removal), permeabilized cell assay","journal":"Cell calcium","confidence":"High","confidence_rationale":"Tier 1 / Moderate — gain- and loss-of-function with pharmacological dissection in permeabilized cells, multiple orthogonal Ca2+ measurement approaches in a single rigorous study","pmids":["19944461"],"is_preprint":false},{"year":2011,"finding":"STOML2 knockdown in glioma cells reduces invasion and migration through inhibition of the NF-κB transcriptional pathway and consequent downregulation of MMP-9. A luciferase reporter assay confirmed the effect on MMP-9 is NF-κB-dependent.","method":"siRNA knockdown, Transwell invasion assay, luciferase NF-κB reporter assay, Western blot for MMP-9 and NF-κB target genes","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pathway placement confirmed by reporter assay plus KD phenotype, single lab","pmids":["21960069"],"is_preprint":false},{"year":2013,"finding":"In C. elegans, the STOML2 orthologue STL-1 (stomatin-like 1) is transcriptionally induced by SKN-1/Nrf in response to anoxia and facilitates mitochondrial dynamics (fission and refusion) following anoxia-reoxygenation. SKN-1 promotes STL-1 expression to support mitochondrial reconstitution during reoxygenation.","method":"C. elegans genetics, transcriptional reporter assays, mitochondrial morphology imaging, epistasis analysis with egl-9, hif-1, skn-1 mutants","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis and transcriptional regulation established by reporter assay and multiple mutant analyses, ortholog study in C. elegans","pmids":["24385935"],"is_preprint":false},{"year":2017,"finding":"SLP-2 physically interacts with Parkin at the mitochondrial level (confirmed by co-immunoprecipitation and proximity ligation assay on endogenous proteins). SLP-2 also binds cardiolipin. Knockdown of SLP-2 decreases respiratory chain complex I activity and alters mitochondrial network morphology. Overexpression of SLP-2 rescues complex I deficiency and mitochondrial morphology in Parkin-deficient cells. In Drosophila, SLP-2 genetically interacts with parkin and its overexpression rescues loss of dopaminergic neurons, mitochondrial structure, ATP production, and motor dysfunction in parkin mutants.","method":"Co-immunoprecipitation, proximity ligation assay (endogenous proteins), siRNA/shRNA knockdown, high-resolution respirometry, mitochondrial imaging, iPSC-derived neuron models, Drosophila genetics and rescue experiments","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — endogenous protein interaction confirmed by PLA and Co-IP, functional epistasis demonstrated in multiple models (SH-SY5Y, iPSC neurons, Drosophila) with multiple orthogonal readouts","pmids":["28379402"],"is_preprint":false},{"year":2021,"finding":"STOML2 interacts with and stabilizes PINK1 under cellular stress, amplifying PINK1-Parkin-mediated mitophagy. HIF-1α transcriptionally upregulates STOML2 expression in HCC cells under lenvatinib treatment. STOML2 co-immunoprecipitates with PINK1.","method":"Co-immunoprecipitation, Western blot, laser confocal microscopy, transmission electron microscopy, ChIP assay, luciferase reporter assay, flow cytometry, gain/loss-of-function experiments","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for STOML2-PINK1 interaction, transcriptional regulation confirmed by ChIP and luciferase assay, single lab","pmids":["33446239"],"is_preprint":false},{"year":2021,"finding":"STOML2 interacts with PHB (prohibitin) and activates the MAPK signaling pathway (RAF1/MEK1/2/ERK1/2 phosphorylation) to promote colorectal cancer proliferation. The interaction was confirmed by co-immunoprecipitation and co-localization by immunofluorescence; yeast two-hybrid initially identified PHB among interactors.","method":"Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence co-localization, Western blot for MAPK pathway components, organoid culture, orthotopic tumor model","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by Co-IP and co-localization; pathway activation shown by phospho-Western; single lab with multiple methods","pmids":["34781982"],"is_preprint":false},{"year":2022,"finding":"CYB5A binds to STOML2 and through this interaction inhibits the JAK1/STAT3 signaling pathway, thereby reducing HCC metastasis.","method":"Co-immunoprecipitation, Western blot, in vitro and in vivo metastasis assays","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for CYB5A-STOML2 interaction, pathway assignment from single lab without full mechanistic dissection","pmids":["35851063"],"is_preprint":false},{"year":2023,"finding":"STOML2 stabilizes PARL (a mitochondrial protease) and thereby prevents PINK1 degradation and PINK1-dependent mitophagy. In pancreatic cancer cells, STOML2 overexpression restricts gemcitabine-induced mitophagy through the PARL/PINK1 pathway.","method":"siRNA/overexpression, Western blot, flow cytometry, mitophagy assays, xenograft models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — mechanistic pathway (STOML2→PARL stabilization→PINK1 degradation) established by KD/OE with Western blot, single lab","pmids":["36906621"],"is_preprint":false},{"year":2024,"finding":"STOML2 binds TRADD protein and through this interaction activates the NF-κB signaling pathway, upregulating CCND1, VEGF, and PD-L1 to promote CRC proliferation, angiogenesis, and immune escape.","method":"Co-immunoprecipitation (STOML2-TRADD), Western blot for NF-κB pathway components, in vitro proliferation/angiogenesis assays, NF-κB inhibitor treatment, in vivo tumor models","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — TRADD interaction confirmed by Co-IP, downstream NF-κB pathway modulation shown by KO/OE and inhibitor rescue, single lab","pmids":["38214751"],"is_preprint":false},{"year":2024,"finding":"The Parkin-SLP-2 interaction maps to the RING0 domain of Parkin. PD-associated PRKN mutations reduce the Parkin-SLP-2 interaction as measured by proximity ligation assay. Three binding sites within RING0 predicted by computational modeling overlap with PD-causing missense mutations. Delivery of the isolated Parkin RING0 domain or a Parkin mini-peptide into Parkin-deficient cells rescues compromised mitochondrial function.","method":"Proximity ligation assay (endogenous proteins), domain mapping with truncation constructs, computational modeling on Parkin crystal structure, high-resolution respirometry, immunofluorescence, live imaging, iPSC-derived neuron models, fibroblasts from PD patients","journal":"Journal of translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — domain mapping combined with structural modeling, functional validation by respirometry in iPSC neurons and patient fibroblasts, PLA quantification; single lab with multiple orthogonal methods","pmids":["38229174"],"is_preprint":false},{"year":2025,"finding":"STOML2 inhibits sorafenib-induced ferroptosis in HCC by activating the AKT-SLC7A11 axis, increasing intracellular antioxidant capacity and reducing lipid peroxidation. AKT inhibitor LY294002 synergizes with sorafenib in STOML2-high HCC cells.","method":"siRNA knockdown, Western blot for AKT/SLC7A11, lipid peroxidation assay (MDA), flow cytometry for ROS/ferroptosis markers, clone formation assay, pharmacological rescue with LY294002","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement (AKT-SLC7A11) supported by KD and pharmacological rescue, single lab, single method per readout","pmids":["40371153"],"is_preprint":false},{"year":2026,"finding":"Under hypoxia, HIF-1α translocates to the nucleus and transcriptionally upregulates STOML2. STOML2 then translocates to the outer mitochondrial membrane and participates in PGAM5 cleavage, triggering PINK1-dependent mitophagy as a neuronal self-protection mechanism. Knockdown of HIF-1α, STOML2, or PGAM5 inhibits this mitophagy and worsens hypoxia-induced neuronal dysfunction.","method":"siRNA knockdown of HIF-1α, STOML2, and PGAM5, overexpression of PINK1, Western blot, immunofluorescence for STOML2 translocation, mitophagy assays, neurological function tests, intermittent hypoxia conditioning","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — transcriptional regulation and protein translocation shown by multiple KD experiments with mechanistic pathway placement, single lab; replicated in preprint","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 ferroptosis. Restoring STOML2 enhances NCLX-dependent Ca2+ handling and improves ATP production in chondrocytes.","method":"Co-immunoprecipitation (STOML2-NCLX), siRNA knockdown, overexpression, mitochondrial Ca2+ imaging, ROS measurement, ATP assay, Seahorse respirometry, intra-articular delivery in rat OA model","journal":"Genetics research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — NCLX interaction shown by Co-IP, functional Ca2+ and metabolic consequences by multiple assays, single lab","pmids":["41995387"],"is_preprint":false},{"year":2026,"finding":"STOML2 and PHB are upregulated in human pluripotent stem cells (hPSCs). STOML2 knockdown reduces OCT4, NANOG, PHB, and phosphorylated ERK levels while increasing differentiation markers, indicating STOML2 maintains hPSC pluripotency and cell cycle integrity through the PHB-ERK/MAPK signaling axis.","method":"shRNA knockdown, qRT-PCR, Western blot for ERK phosphorylation and pluripotency markers, transcriptomic profiling","journal":"International journal of stem cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement (STOML2-PHB-ERK) inferred from KD and expression data, no direct interaction assay reported in abstract, single lab","pmids":["41709508"],"is_preprint":false},{"year":2025,"finding":"SLP-2 levels are reduced in human PD brains and in an A53T αSyn mouse model. Mild overexpression of SLP-2 improves mitochondrial function, reduces oxidative stress, prevents αSyn-mitochondria interactions in iPSC-derived neurons, and protects dopaminergic neurons and motor function in vivo. SLP-2 depletion exacerbates neurodegeneration and motor deficits in both mouse and Drosophila models.","method":"Immunohistochemistry/Western blot in human PD brain and mouse model, SLP-2 overexpression and depletion in iPSC-derived neurons, mitochondrial function assays, ROS measurement, proximity/co-localization for αSyn-mitochondria interaction, in vivo mouse and Drosophila experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple models (iPSC neurons, mouse, Drosophila) with orthogonal functional readouts; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"STOML2 is a mitochondrial inner membrane scaffold protein that stabilizes prohibitins and respiratory chain complex subunits, is required for stress-induced mitochondrial hyperfusion (via L-OPA1/MFN1), negatively regulates mitochondrial Na+/Ca2+ exchange (and a parallel NCLX-dependent Ca2+ efflux axis), modulates PINK1-dependent mitophagy (both by stabilizing PINK1 through PARL and by translocating to the outer membrane to assist PGAM5 cleavage under HIF-1α induction), physically interacts with Parkin (via the Parkin RING0 domain) to support respiratory chain complex I activity, and activates MAPK/ERK signaling through its interaction with prohibitin, collectively linking mitochondrial integrity, dynamics, and energy metabolism to cell survival and proliferation."},"narrative":{"mechanistic_narrative":"STOML2 (SLP-2) is a stomatin-family protein that functions principally as a mitochondrial inner-membrane scaffold coupling mitochondrial integrity, dynamics, and energy metabolism to cell survival and proliferation [PMID:18339324, PMID:19360003]. It associates strongly with the inner membrane and binds cardiolipin, physically interacting with prohibitins (PHB1/PHB2) and stabilizing them along with subunits of respiratory chain complexes I and IV against proteolysis [PMID:18339324, PMID:28379402]. Through this scaffolding role STOML2 is required for stress-induced mitochondrial hyperfusion, an MFN1- and L-OPA1-dependent pro-survival response, and its loss abolishes hyperfusion and depletes L-OPA1 while lowering membrane potential and ATP output [PMID:19360003, PMID:19597348]. STOML2 negatively modulates mitochondrial Ca2+ efflux, restraining the Na+/Ca2+ exchanger and supporting NCLX-dependent Ca2+ handling and oxidative phosphorylation [PMID:19944461, PMID:41995387]. It integrates with the PINK1-Parkin axis on multiple levels: it physically interacts with Parkin through the Parkin RING0 domain to support complex I activity and mitochondrial morphology, with this interaction disrupted by PD-associated PRKN mutations [PMID:28379402, PMID:38229174], and it controls PINK1-dependent mitophagy both by stabilizing PARL to limit PINK1 degradation and, under HIF-1α induction during hypoxia, by translocating to the outer membrane to participate in PGAM5 cleavage [PMID:36906621, PMID:41723145]. Beyond mitochondria, STOML2 drives proliferative and pro-survival signaling, activating MAPK/ERK through prohibitin and NF-κB signaling, the latter via TRADD, to promote tumor growth and migration [PMID:34781982, PMID:38214751]. STOML2 protects against neurodegeneration in Parkinson's disease models, where its overexpression preserves dopaminergic neurons and motor function and its loss exacerbates deficits [PMID:38229174].","teleology":[{"year":2000,"claim":"Established STOML2 as a stomatin homologue that, unlike other family members, lacks the N-terminal hydrophobic domain and associates with membranes peripherally rather than as an integral protein, framing it as a cytoskeleton-linked scaffold.","evidence":"Cloning, NaOH/Triton X-100 fractionation, and expression in COS cells from erythrocytes","pmids":["10713127"],"confidence":"Medium","gaps":["Subcellular compartment beyond erythrocyte cytoskeleton not defined","No functional consequence established"]},{"year":2008,"claim":"Placed STOML2 at the mitochondrial inner membrane as a stabilizing scaffold for prohibitins and respiratory chain subunits, answering where it acts and giving it a concrete biochemical role.","evidence":"Proteomic fractionation, reciprocal Co-IP, and siRNA knockdown in HeLa cells","pmids":["18339324"],"confidence":"High","gaps":["Mechanism of protein stabilization not defined","Direct vs indirect protection of complex subunits unresolved"]},{"year":2009,"claim":"Showed STOML2 is required for stress-induced mitochondrial hyperfusion and bioenergetic adaptation, linking the scaffold to mitochondrial dynamics and pro-survival ATP output.","evidence":"siRNA knockdown, mitochondrial morphology imaging, OPA1 immunoblot, ATP assays, and epistasis with MFN1/L-OPA1 in stressed cells","pmids":["19360003","19597348"],"confidence":"High","gaps":["How STOML2 promotes L-OPA1 stability mechanistically unclear","Connection between hyperfusion and complex stabilization not dissected"]},{"year":2009,"claim":"Identified STOML2 as a negative regulator of mitochondrial Na+/Ca2+ exchange, extending its role to ion handling and Ca2+ retention.","evidence":"Gain- and loss-of-function with mitochondrial Ca2+ imaging and pharmacological NCX inhibition in permeabilized HeLa cells","pmids":["19944461"],"confidence":"High","gaps":["Molecular target of STOML2 in the exchange machinery not identified at this stage","Whether effect is direct binding or membrane organization unresolved"]},{"year":2011,"claim":"Connected STOML2 to NF-κB-driven invasion via MMP-9, extending the protein into pro-tumorigenic signaling beyond mitochondria.","evidence":"siRNA knockdown, Transwell assays, and NF-κB luciferase reporter in glioma cells","pmids":["21960069"],"confidence":"Medium","gaps":["No direct molecular link between STOML2 and NF-κB defined here","Mechanism connecting mitochondrial scaffold to nuclear signaling unknown"]},{"year":2013,"claim":"Showed the STOML2 ortholog is transcriptionally induced by SKN-1/Nrf under anoxia to support mitochondrial dynamics during reoxygenation, establishing a conserved stress-responsive role.","evidence":"C. elegans genetics, transcriptional reporters, and morphology imaging with egl-9/hif-1/skn-1 epistasis","pmids":["24385935"],"confidence":"Medium","gaps":["Direct relevance of transcriptional regulation to mammalian STOML2 not tested here","Effector mechanism downstream of induction unclear"]},{"year":2017,"claim":"Demonstrated a direct STOML2-Parkin interaction supporting complex I activity, integrating STOML2 into Parkinson's disease-relevant mitochondrial quality control across multiple model systems.","evidence":"Endogenous Co-IP and PLA, respirometry, cardiolipin binding, iPSC neurons, and Drosophila parkin rescue genetics","pmids":["28379402"],"confidence":"High","gaps":["Binding interface on Parkin not yet mapped at this stage","Relationship to PINK1-Parkin mitophagy not addressed"]},{"year":2021,"claim":"Revealed STOML2 as a regulator of PINK1-Parkin mitophagy and a HIF-1α-induced stress effector, linking it to chemoresistance in cancer.","evidence":"Co-IP with PINK1, ChIP and luciferase for HIF-1α regulation, microscopy and flow cytometry in HCC cells under lenvatinib","pmids":["33446239"],"confidence":"Medium","gaps":["Whether STOML2 stabilizes PINK1 directly or via a partner unresolved here","In vivo relevance limited"]},{"year":2021,"claim":"Mapped a STOML2-prohibitin-MAPK/ERK axis driving cancer proliferation, providing a direct molecular route from STOML2 to ERK signaling.","evidence":"Yeast two-hybrid, Co-IP, immunofluorescence colocalization, phospho-Western for RAF1/MEK/ERK, organoid and orthotopic models in colorectal cancer","pmids":["34781982"],"confidence":"Medium","gaps":["How prohibitin binding triggers RAF1 activation not dissected","Subcellular site of MAPK activation unclear"]},{"year":2022,"claim":"Identified CYB5A as a STOML2 binding partner that suppresses JAK1/STAT3 signaling, positioning STOML2 within metastasis-suppressive regulation.","evidence":"Co-IP and metastasis assays in HCC","pmids":["35851063"],"confidence":"Low","gaps":["Single Co-IP without reciprocal or structural validation","Mechanism by which the interaction modulates JAK1/STAT3 not established"]},{"year":2023,"claim":"Defined a STOML2→PARL stabilization→PINK1 degradation pathway that restricts mitophagy, refining how STOML2 controls PINK1 turnover.","evidence":"Knockdown/overexpression, Western blot, mitophagy assays, and xenografts in pancreatic cancer cells","pmids":["36906621"],"confidence":"Medium","gaps":["Direct STOML2-PARL binding not shown","Reconciliation with PINK1 stabilization reports not addressed"]},{"year":2024,"claim":"Provided structural and genetic specificity by mapping the STOML2-Parkin interaction to the Parkin RING0 domain and showing PD mutations disrupt it, with isolated RING0 rescuing mitochondrial function.","evidence":"PLA quantification, truncation domain mapping, structural modeling, respirometry, iPSC neurons, and PD patient fibroblasts","pmids":["38229174"],"confidence":"High","gaps":["STOML2 residues contacting RING0 not defined","Therapeutic peptide delivery validated only in cell models"]},{"year":2024,"claim":"Showed STOML2 binds TRADD to activate NF-κB and upregulate CCND1, VEGF, and PD-L1, providing a direct adaptor link to NF-κB-driven proliferation, angiogenesis, and immune escape.","evidence":"Co-IP, NF-κB phospho-Western, inhibitor rescue, and in vivo tumor models in colorectal cancer","pmids":["38214751"],"confidence":"Medium","gaps":["How a mitochondrial scaffold accesses TRADD signaling not resolved","Direct vs indirect NF-κB activation not separated"]},{"year":2025,"claim":"Linked STOML2 to ferroptosis resistance via the AKT-SLC7A11 antioxidant axis in HCC.","evidence":"siRNA knockdown, AKT/SLC7A11 Western blot, lipid peroxidation and ROS assays, and LY294002 rescue","pmids":["40371153"],"confidence":"Low","gaps":["Pathway placement from KD and pharmacology only, single method per readout","No direct molecular connector to AKT identified"]},{"year":2025,"claim":"Provided in vivo evidence that STOML2 is neuroprotective in Parkinson's disease models, with reduced levels in PD brains and overexpression preserving dopaminergic neurons.","evidence":"Human PD brain and A53T αSyn mouse analysis, iPSC neuron gain/loss-of-function, and Drosophila models (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Mechanism preventing αSyn-mitochondria interaction not fully defined"]},{"year":2026,"claim":"Identified NCLX as a STOML2 interaction partner supporting Ca2+ efflux and metabolic stability, refining the earlier Ca2+ exchange phenotype into a specific molecular partnership relevant to senescence and ferroptosis.","evidence":"Co-IP with NCLX, Ca2+ imaging, Seahorse respirometry, and rat OA model in chondrocytes","pmids":["41995387"],"confidence":"Medium","gaps":["Reconciliation with earlier negative-regulation of Na+/Ca2+ exchange not addressed","Direct binding interface not mapped"]},{"year":2026,"claim":"Showed HIF-1α transcriptionally induces STOML2, which then translocates to the outer mitochondrial membrane to participate in PGAM5 cleavage and PINK1-dependent mitophagy as a neuronal protective response to hypoxia.","evidence":"siRNA knockdown of HIF-1α/STOML2/PGAM5, PINK1 overexpression, translocation immunofluorescence, and mitophagy/neurological assays under intermittent hypoxia","pmids":["41723145"],"confidence":"Medium","gaps":["How an inner-membrane scaffold relocates to the outer membrane not explained","Direct STOML2-PGAM5 interaction not shown"]},{"year":null,"claim":"How STOML2 mechanistically bridges its inner-membrane scaffolding role to cytosolic/nuclear signaling (NF-κB, MAPK, AKT) and reconciles its dual stabilizing-vs-degrading effects on PINK1 remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of STOML2 in its membrane scaffold complex","Mechanism of STOML2 trafficking between inner and outer membrane unknown","Whether signaling functions are direct or secondary to mitochondrial state undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[1,2,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,11,16]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,2,3,7]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8,11,15]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,12]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,15]}],"complexes":[],"partners":["PHB1","PHB2","PARKIN","PINK1","PARL","NCLX","TRADD","CYB5A"],"other_free_text":[]}},"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":630,"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":143,"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":76,"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":50,"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":"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":40,"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":"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 calcium","url":"https://pubmed.ncbi.nlm.nih.gov/19944461","citation_count":28,"is_preprint":false},{"pmid":"11435687","id":"PMC_11435687","title":"A novel member of the STOMATIN/EPB72/mec-2 family, stomatin-like 2 (STOML2), is ubiquitously expressed and localizes to HSA chromosome 9p13.1.","date":"2001","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11435687","citation_count":22,"is_preprint":false},{"pmid":"31290903","id":"PMC_31290903","title":"Alginate oligosaccharide (AOS) improves immuno-metabolic systems by inhibiting STOML2 overexpression in high-fat-diet-induced obese zebrafish.","date":"2019","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/31290903","citation_count":22,"is_preprint":false},{"pmid":"29951933","id":"PMC_29951933","title":"The diagnostic value of TROP-2, SLP-2 and CD56 expression in papillary thyroid carcinoma.","date":"2018","source":"European archives of oto-rhino-laryngology : official journal of the European 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":"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":18,"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":"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":"37840424","id":"PMC_37840424","title":"Resveratrol augments paclitaxel sensitivity by modulating miR-671-5p/STOML2/PINK1/Parkin-mediated autophagy signaling in A549 cell.","date":"2023","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/37840424","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 letters","url":"https://pubmed.ncbi.nlm.nih.gov/30944651","citation_count":11,"is_preprint":false},{"pmid":"15694024","id":"PMC_15694024","title":"[Effect of stomatin-like protein 2 (SLP-2) gene on growth and proliferation of esophageal squamous carcinoma cell line TE12].","date":"2005","source":"Ai zheng = Aizheng = Chinese journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15694024","citation_count":11,"is_preprint":false},{"pmid":"16671055","id":"PMC_16671055","title":"Mass spectrometrical verification of stomatin-like protein 2 (SLP-2) primary 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":"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":1,"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":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":"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":"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":"42142700","id":"PMC_42142700","title":"Single-cell and spatial analyses identify a glycolysis-high state driven by STOML2 in epithelial ovarian cancer.","date":"2026","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/42142700","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":"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":"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":"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_2025.06.13.659577","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":25712,"output_tokens":5169,"usd":0.077336,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13602,"output_tokens":5330,"usd":0.10063,"stage2_stop_reason":"end_turn"},"total_usd":0.177966,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"SLP-2 (STOML2) was identified as a novel stomatin homologue present in erythrocytes and other tissues. It lacks the N-terminal hydrophobic domain of other stomatin homologues, is fully extractable from membranes by NaOH (pH 11), and partitions into both Triton X-100-soluble and -insoluble pools. It was shown to interact with the peripheral erythrocyte cytoskeleton but not directly with the membrane bilayer.\",\n      \"method\": \"Cloning, Western blot, SDS-PAGE, NaOH extraction, Triton X-100 fractionation, expression in COS cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation and membrane extraction with two orthogonal methods in a single founding study\",\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 of subunits of respiratory chain complexes I and IV, indicating SLP-2 stabilizes these proteins.\",\n      \"method\": \"Proteomic fractionation, co-immunoprecipitation, SLP-2 siRNA knockdown, Western blot for prohibitin and respiratory chain subunit levels\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal protein interaction confirmed by Co-IP, functional consequence (proteolysis) demonstrated by KD with two orthogonal readouts in a single focused study\",\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 cells exposed to selective stresses (UV irradiation, actinomycin D), mitochondria hyperfuse in an MFN1- and L-OPA1-dependent manner; depletion of SLP-2 abolishes SIMH and causes loss of L-OPA1. SIMH is accompanied by increased mitochondrial ATP production and represents a pro-survival adaptive response.\",\n      \"method\": \"SLP-2 siRNA knockdown, mitochondrial morphology imaging, immunoblot for OPA1 isoforms, ATP production assay, epistasis with MFN1/MFN2/BAX/BAK/prohibitin knockdowns\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis plus multiple orthogonal phenotypic readouts (morphology, OPA1 processing, ATP), replicated across stress conditions\",\n      \"pmids\": [\"19360003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SLP-2 localizes to mitochondria, where it affects mitochondrial membrane potential (MMP) and ATP production. Knockdown of SLP-2 by siRNA inhibits cell motility, proliferation, and enhances chemosensitivity, with decreased MMP and ATP levels.\",\n      \"method\": \"siRNA knockdown, mitochondrial membrane potential assay, ATP production assay, immunofluorescence localization, proliferation and motility assays\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct mitochondrial localization confirmed by immunofluorescence, functional consequence of KD shown by two biochemical readouts (MMP, ATP), single lab\",\n      \"pmids\": [\"19597348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SLP-2 negatively modulates mitochondrial sodium-calcium exchange (Na+/Ca2+ exchanger). SLP-2 depletion in HeLa cells increased rates of mitochondrial Ca2+ extrusion via the Na+/Ca2+ exchanger, an effect blocked by Na+ removal or CGP-37157 (NCX inhibitor). SLP-2 overexpression prolonged mitochondrial Ca2+ retention and decreased cytosolic Ca2+ elevations.\",\n      \"method\": \"siRNA knockdown, SLP-2 overexpression, mitochondrial Ca2+ imaging, pharmacological inhibition (CGP-37157, Na+ removal), permeabilized cell assay\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — gain- and loss-of-function with pharmacological dissection in permeabilized cells, multiple orthogonal Ca2+ measurement approaches in a single rigorous study\",\n      \"pmids\": [\"19944461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STOML2 knockdown in glioma cells reduces invasion and migration through inhibition of the NF-κB transcriptional pathway and consequent downregulation of MMP-9. A luciferase reporter assay confirmed the effect on MMP-9 is NF-κB-dependent.\",\n      \"method\": \"siRNA knockdown, Transwell invasion assay, luciferase NF-κB reporter assay, Western blot for MMP-9 and NF-κB target genes\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pathway placement confirmed by reporter assay plus KD phenotype, single lab\",\n      \"pmids\": [\"21960069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In C. elegans, the STOML2 orthologue STL-1 (stomatin-like 1) is transcriptionally induced by SKN-1/Nrf in response to anoxia and facilitates mitochondrial dynamics (fission and refusion) following anoxia-reoxygenation. SKN-1 promotes STL-1 expression to support mitochondrial reconstitution during reoxygenation.\",\n      \"method\": \"C. elegans genetics, transcriptional reporter assays, mitochondrial morphology imaging, epistasis analysis with egl-9, hif-1, skn-1 mutants\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis and transcriptional regulation established by reporter assay and multiple mutant analyses, ortholog study in C. elegans\",\n      \"pmids\": [\"24385935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SLP-2 physically interacts with Parkin at the mitochondrial level (confirmed by co-immunoprecipitation and proximity ligation assay on endogenous proteins). SLP-2 also binds cardiolipin. Knockdown of SLP-2 decreases respiratory chain complex I activity and alters mitochondrial network morphology. Overexpression of SLP-2 rescues complex I deficiency and mitochondrial morphology in Parkin-deficient cells. In Drosophila, SLP-2 genetically interacts with parkin and its overexpression rescues loss of dopaminergic neurons, mitochondrial structure, ATP production, and motor dysfunction in parkin mutants.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay (endogenous proteins), siRNA/shRNA knockdown, high-resolution respirometry, mitochondrial imaging, iPSC-derived neuron models, Drosophila genetics and rescue experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — endogenous protein interaction confirmed by PLA and Co-IP, functional epistasis demonstrated in multiple models (SH-SY5Y, iPSC neurons, Drosophila) with multiple orthogonal readouts\",\n      \"pmids\": [\"28379402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STOML2 interacts with and stabilizes PINK1 under cellular stress, amplifying PINK1-Parkin-mediated mitophagy. HIF-1α transcriptionally upregulates STOML2 expression in HCC cells under lenvatinib treatment. STOML2 co-immunoprecipitates with PINK1.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, laser confocal microscopy, transmission electron microscopy, ChIP assay, luciferase reporter assay, flow cytometry, gain/loss-of-function experiments\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for STOML2-PINK1 interaction, transcriptional regulation confirmed by ChIP and luciferase assay, single lab\",\n      \"pmids\": [\"33446239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STOML2 interacts with PHB (prohibitin) and activates the MAPK signaling pathway (RAF1/MEK1/2/ERK1/2 phosphorylation) to promote colorectal cancer proliferation. The interaction was confirmed by co-immunoprecipitation and co-localization by immunofluorescence; yeast two-hybrid initially identified PHB among interactors.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence co-localization, Western blot for MAPK pathway components, organoid culture, orthotopic tumor model\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by Co-IP and co-localization; pathway activation shown by phospho-Western; single lab with multiple methods\",\n      \"pmids\": [\"34781982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CYB5A binds to STOML2 and through this interaction inhibits the JAK1/STAT3 signaling pathway, thereby reducing HCC metastasis.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, in vitro and in vivo metastasis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for CYB5A-STOML2 interaction, pathway assignment from single lab without full mechanistic dissection\",\n      \"pmids\": [\"35851063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STOML2 stabilizes PARL (a mitochondrial protease) and thereby prevents PINK1 degradation and PINK1-dependent mitophagy. In pancreatic cancer cells, STOML2 overexpression restricts gemcitabine-induced mitophagy through the PARL/PINK1 pathway.\",\n      \"method\": \"siRNA/overexpression, Western blot, flow cytometry, mitophagy assays, xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mechanistic pathway (STOML2→PARL stabilization→PINK1 degradation) established by KD/OE with Western blot, single lab\",\n      \"pmids\": [\"36906621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STOML2 binds TRADD protein and through this interaction activates the NF-κB signaling pathway, upregulating CCND1, VEGF, and PD-L1 to promote CRC proliferation, angiogenesis, and immune escape.\",\n      \"method\": \"Co-immunoprecipitation (STOML2-TRADD), Western blot for NF-κB pathway components, in vitro proliferation/angiogenesis assays, NF-κB inhibitor treatment, in vivo tumor models\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — TRADD interaction confirmed by Co-IP, downstream NF-κB pathway modulation shown by KO/OE and inhibitor rescue, single lab\",\n      \"pmids\": [\"38214751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The Parkin-SLP-2 interaction maps to the RING0 domain of Parkin. PD-associated PRKN mutations reduce the Parkin-SLP-2 interaction as measured by proximity ligation assay. Three binding sites within RING0 predicted by computational modeling overlap with PD-causing missense mutations. Delivery of the isolated Parkin RING0 domain or a Parkin mini-peptide into Parkin-deficient cells rescues compromised mitochondrial function.\",\n      \"method\": \"Proximity ligation assay (endogenous proteins), domain mapping with truncation constructs, computational modeling on Parkin crystal structure, high-resolution respirometry, immunofluorescence, live imaging, iPSC-derived neuron models, fibroblasts from PD patients\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — domain mapping combined with structural modeling, functional validation by respirometry in iPSC neurons and patient fibroblasts, PLA quantification; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38229174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STOML2 inhibits sorafenib-induced ferroptosis in HCC by activating the AKT-SLC7A11 axis, increasing intracellular antioxidant capacity and reducing lipid peroxidation. AKT inhibitor LY294002 synergizes with sorafenib in STOML2-high HCC cells.\",\n      \"method\": \"siRNA knockdown, Western blot for AKT/SLC7A11, lipid peroxidation assay (MDA), flow cytometry for ROS/ferroptosis markers, clone formation assay, pharmacological rescue with LY294002\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement (AKT-SLC7A11) supported by KD and pharmacological rescue, single lab, single method per readout\",\n      \"pmids\": [\"40371153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Under hypoxia, HIF-1α translocates to the nucleus and transcriptionally upregulates STOML2. STOML2 then translocates to the outer mitochondrial membrane and participates in PGAM5 cleavage, triggering PINK1-dependent mitophagy as a neuronal self-protection mechanism. Knockdown of HIF-1α, STOML2, or PGAM5 inhibits this mitophagy and worsens hypoxia-induced neuronal dysfunction.\",\n      \"method\": \"siRNA knockdown of HIF-1α, STOML2, and PGAM5, overexpression of PINK1, Western blot, immunofluorescence for STOML2 translocation, mitophagy assays, neurological function tests, intermittent hypoxia conditioning\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — transcriptional regulation and protein translocation shown by multiple KD experiments with mechanistic pathway placement, single lab; replicated in preprint\",\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 ferroptosis. Restoring STOML2 enhances NCLX-dependent Ca2+ handling and improves ATP production in chondrocytes.\",\n      \"method\": \"Co-immunoprecipitation (STOML2-NCLX), siRNA knockdown, overexpression, mitochondrial Ca2+ imaging, ROS measurement, ATP assay, Seahorse respirometry, intra-articular delivery in rat OA model\",\n      \"journal\": \"Genetics research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — NCLX interaction shown by Co-IP, functional Ca2+ and metabolic consequences by multiple assays, single lab\",\n      \"pmids\": [\"41995387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STOML2 and PHB are upregulated in human pluripotent stem cells (hPSCs). STOML2 knockdown reduces OCT4, NANOG, PHB, and phosphorylated ERK levels while increasing differentiation markers, indicating STOML2 maintains hPSC pluripotency and cell cycle integrity through the PHB-ERK/MAPK signaling axis.\",\n      \"method\": \"shRNA knockdown, qRT-PCR, Western blot for ERK phosphorylation and pluripotency markers, transcriptomic profiling\",\n      \"journal\": \"International journal of stem cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement (STOML2-PHB-ERK) inferred from KD and expression data, no direct interaction assay reported in abstract, single lab\",\n      \"pmids\": [\"41709508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLP-2 levels are reduced in human PD brains and in an A53T αSyn mouse model. Mild overexpression of SLP-2 improves mitochondrial function, reduces oxidative stress, prevents αSyn-mitochondria interactions in iPSC-derived neurons, and protects dopaminergic neurons and motor function in vivo. SLP-2 depletion exacerbates neurodegeneration and motor deficits in both mouse and Drosophila models.\",\n      \"method\": \"Immunohistochemistry/Western blot in human PD brain and mouse model, SLP-2 overexpression and depletion in iPSC-derived neurons, mitochondrial function assays, ROS measurement, proximity/co-localization for αSyn-mitochondria interaction, in vivo mouse and Drosophila experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple models (iPSC neurons, mouse, Drosophila) with orthogonal functional readouts; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"STOML2 is a mitochondrial inner membrane scaffold protein that stabilizes prohibitins and respiratory chain complex subunits, is required for stress-induced mitochondrial hyperfusion (via L-OPA1/MFN1), negatively regulates mitochondrial Na+/Ca2+ exchange (and a parallel NCLX-dependent Ca2+ efflux axis), modulates PINK1-dependent mitophagy (both by stabilizing PINK1 through PARL and by translocating to the outer membrane to assist PGAM5 cleavage under HIF-1α induction), physically interacts with Parkin (via the Parkin RING0 domain) to support respiratory chain complex I activity, and activates MAPK/ERK signaling through its interaction with prohibitin, collectively linking mitochondrial integrity, dynamics, and energy metabolism to cell survival and proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STOML2 (SLP-2) is a stomatin-family protein that functions principally as a mitochondrial inner-membrane scaffold coupling mitochondrial integrity, dynamics, and energy metabolism to cell survival and proliferation [#1, #2]. It associates strongly with the inner membrane and binds cardiolipin, physically interacting with prohibitins (PHB1/PHB2) and stabilizing them along with subunits of respiratory chain complexes I and IV against proteolysis [#1, #7]. Through this scaffolding role STOML2 is required for stress-induced mitochondrial hyperfusion, an MFN1- and L-OPA1-dependent pro-survival response, and its loss abolishes hyperfusion and depletes L-OPA1 while lowering membrane potential and ATP output [#2, #3]. STOML2 negatively modulates mitochondrial Ca2+ efflux, restraining the Na+/Ca2+ exchanger and supporting NCLX-dependent Ca2+ handling and oxidative phosphorylation [#4, #16]. It integrates with the PINK1-Parkin axis on multiple levels: it physically interacts with Parkin through the Parkin RING0 domain to support complex I activity and mitochondrial morphology, with this interaction disrupted by PD-associated PRKN mutations [#7, #13], and it controls PINK1-dependent mitophagy both by stabilizing PARL to limit PINK1 degradation and, under HIF-1\\u03b1 induction during hypoxia, by translocating to the outer membrane to participate in PGAM5 cleavage [#11, #15]. Beyond mitochondria, STOML2 drives proliferative and pro-survival signaling, activating MAPK/ERK through prohibitin and NF-\\u03baB signaling, the latter via TRADD, to promote tumor growth and migration [#9, #12]. STOML2 protects against neurodegeneration in Parkinson's disease models, where its overexpression preserves dopaminergic neurons and motor function and its loss exacerbates deficits [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established STOML2 as a stomatin homologue that, unlike other family members, lacks the N-terminal hydrophobic domain and associates with membranes peripherally rather than as an integral protein, framing it as a cytoskeleton-linked scaffold.\",\n      \"evidence\": \"Cloning, NaOH/Triton X-100 fractionation, and expression in COS cells from erythrocytes\",\n      \"pmids\": [\"10713127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Subcellular compartment beyond erythrocyte cytoskeleton not defined\", \"No functional consequence established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed STOML2 at the mitochondrial inner membrane as a stabilizing scaffold for prohibitins and respiratory chain subunits, answering where it acts and giving it a concrete biochemical role.\",\n      \"evidence\": \"Proteomic fractionation, reciprocal Co-IP, and siRNA knockdown in HeLa cells\",\n      \"pmids\": [\"18339324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of protein stabilization not defined\", \"Direct vs indirect protection of complex subunits unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed STOML2 is required for stress-induced mitochondrial hyperfusion and bioenergetic adaptation, linking the scaffold to mitochondrial dynamics and pro-survival ATP output.\",\n      \"evidence\": \"siRNA knockdown, mitochondrial morphology imaging, OPA1 immunoblot, ATP assays, and epistasis with MFN1/L-OPA1 in stressed cells\",\n      \"pmids\": [\"19360003\", \"19597348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How STOML2 promotes L-OPA1 stability mechanistically unclear\", \"Connection between hyperfusion and complex stabilization not dissected\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified STOML2 as a negative regulator of mitochondrial Na+/Ca2+ exchange, extending its role to ion handling and Ca2+ retention.\",\n      \"evidence\": \"Gain- and loss-of-function with mitochondrial Ca2+ imaging and pharmacological NCX inhibition in permeabilized HeLa cells\",\n      \"pmids\": [\"19944461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target of STOML2 in the exchange machinery not identified at this stage\", \"Whether effect is direct binding or membrane organization unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected STOML2 to NF-\\u03baB-driven invasion via MMP-9, extending the protein into pro-tumorigenic signaling beyond mitochondria.\",\n      \"evidence\": \"siRNA knockdown, Transwell assays, and NF-\\u03baB luciferase reporter in glioma cells\",\n      \"pmids\": [\"21960069\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct molecular link between STOML2 and NF-\\u03baB defined here\", \"Mechanism connecting mitochondrial scaffold to nuclear signaling unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed the STOML2 ortholog is transcriptionally induced by SKN-1/Nrf under anoxia to support mitochondrial dynamics during reoxygenation, establishing a conserved stress-responsive role.\",\n      \"evidence\": \"C. elegans genetics, transcriptional reporters, and morphology imaging with egl-9/hif-1/skn-1 epistasis\",\n      \"pmids\": [\"24385935\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct relevance of transcriptional regulation to mammalian STOML2 not tested here\", \"Effector mechanism downstream of induction unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a direct STOML2-Parkin interaction supporting complex I activity, integrating STOML2 into Parkinson's disease-relevant mitochondrial quality control across multiple model systems.\",\n      \"evidence\": \"Endogenous Co-IP and PLA, respirometry, cardiolipin binding, iPSC neurons, and Drosophila parkin rescue genetics\",\n      \"pmids\": [\"28379402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface on Parkin not yet mapped at this stage\", \"Relationship to PINK1-Parkin mitophagy not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed STOML2 as a regulator of PINK1-Parkin mitophagy and a HIF-1\\u03b1-induced stress effector, linking it to chemoresistance in cancer.\",\n      \"evidence\": \"Co-IP with PINK1, ChIP and luciferase for HIF-1\\u03b1 regulation, microscopy and flow cytometry in HCC cells under lenvatinib\",\n      \"pmids\": [\"33446239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STOML2 stabilizes PINK1 directly or via a partner unresolved here\", \"In vivo relevance limited\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped a STOML2-prohibitin-MAPK/ERK axis driving cancer proliferation, providing a direct molecular route from STOML2 to ERK signaling.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, immunofluorescence colocalization, phospho-Western for RAF1/MEK/ERK, organoid and orthotopic models in colorectal cancer\",\n      \"pmids\": [\"34781982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How prohibitin binding triggers RAF1 activation not dissected\", \"Subcellular site of MAPK activation unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified CYB5A as a STOML2 binding partner that suppresses JAK1/STAT3 signaling, positioning STOML2 within metastasis-suppressive regulation.\",\n      \"evidence\": \"Co-IP and metastasis assays in HCC\",\n      \"pmids\": [\"35851063\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal or structural validation\", \"Mechanism by which the interaction modulates JAK1/STAT3 not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a STOML2\\u2192PARL stabilization\\u2192PINK1 degradation pathway that restricts mitophagy, refining how STOML2 controls PINK1 turnover.\",\n      \"evidence\": \"Knockdown/overexpression, Western blot, mitophagy assays, and xenografts in pancreatic cancer cells\",\n      \"pmids\": [\"36906621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STOML2-PARL binding not shown\", \"Reconciliation with PINK1 stabilization reports not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided structural and genetic specificity by mapping the STOML2-Parkin interaction to the Parkin RING0 domain and showing PD mutations disrupt it, with isolated RING0 rescuing mitochondrial function.\",\n      \"evidence\": \"PLA quantification, truncation domain mapping, structural modeling, respirometry, iPSC neurons, and PD patient fibroblasts\",\n      \"pmids\": [\"38229174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"STOML2 residues contacting RING0 not defined\", \"Therapeutic peptide delivery validated only in cell models\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed STOML2 binds TRADD to activate NF-\\u03baB and upregulate CCND1, VEGF, and PD-L1, providing a direct adaptor link to NF-\\u03baB-driven proliferation, angiogenesis, and immune escape.\",\n      \"evidence\": \"Co-IP, NF-\\u03baB phospho-Western, inhibitor rescue, and in vivo tumor models in colorectal cancer\",\n      \"pmids\": [\"38214751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a mitochondrial scaffold accesses TRADD signaling not resolved\", \"Direct vs indirect NF-\\u03baB activation not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked STOML2 to ferroptosis resistance via the AKT-SLC7A11 antioxidant axis in HCC.\",\n      \"evidence\": \"siRNA knockdown, AKT/SLC7A11 Western blot, lipid peroxidation and ROS assays, and LY294002 rescue\",\n      \"pmids\": [\"40371153\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement from KD and pharmacology only, single method per readout\", \"No direct molecular connector to AKT identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided in vivo evidence that STOML2 is neuroprotective in Parkinson's disease models, with reduced levels in PD brains and overexpression preserving dopaminergic neurons.\",\n      \"evidence\": \"Human PD brain and A53T \\u03b1Syn mouse analysis, iPSC neuron gain/loss-of-function, and Drosophila models (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Mechanism preventing \\u03b1Syn-mitochondria interaction not fully defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified NCLX as a STOML2 interaction partner supporting Ca2+ efflux and metabolic stability, refining the earlier Ca2+ exchange phenotype into a specific molecular partnership relevant to senescence and ferroptosis.\",\n      \"evidence\": \"Co-IP with NCLX, Ca2+ imaging, Seahorse respirometry, and rat OA model in chondrocytes\",\n      \"pmids\": [\"41995387\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with earlier negative-regulation of Na+/Ca2+ exchange not addressed\", \"Direct binding interface not mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed HIF-1\\u03b1 transcriptionally induces STOML2, which then translocates to the outer mitochondrial membrane to participate in PGAM5 cleavage and PINK1-dependent mitophagy as a neuronal protective response to hypoxia.\",\n      \"evidence\": \"siRNA knockdown of HIF-1\\u03b1/STOML2/PGAM5, PINK1 overexpression, translocation immunofluorescence, and mitophagy/neurological assays under intermittent hypoxia\",\n      \"pmids\": [\"41723145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How an inner-membrane scaffold relocates to the outer membrane not explained\", \"Direct STOML2-PGAM5 interaction not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How STOML2 mechanistically bridges its inner-membrane scaffolding role to cytosolic/nuclear signaling (NF-\\u03baB, MAPK, AKT) and reconciles its dual stabilizing-vs-degrading effects on PINK1 remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of STOML2 in its membrane scaffold complex\", \"Mechanism of STOML2 trafficking between inner and outer membrane unknown\", \"Whether signaling functions are direct or secondary to mitochondrial state undetermined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [1, 2, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 11, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 2, 3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8, 11, 15]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 12]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PHB1\", \"PHB2\", \"Parkin\", \"PINK1\", \"PARL\", \"NCLX\", \"TRADD\", \"CYB5A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}