{"gene":"SDHA","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2020,"finding":"X-ray crystal structure of human SDHA in complex with its dedicated assembly factor SDHAF2 was determined. A small-molecule dicarboxylate acts as an essential cofactor that works in synergy with SDHAF2 to orient the flavin and capping domains of SDHA, reorganizing the active site and adjusting the pKa of SDHA R451 to support covalent attachment of the FAD cofactor. Four distinct conformational forms of the complex II flavoprotein were identified and assigned to roles in assembly and catalysis.","method":"X-ray crystallography, biochemical reconstitution, structural studies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — X-ray structure combined with biochemical reconstitution and mutagenesis in a single rigorous study; multiple orthogonal methods","pmids":["32887801"],"is_preprint":false},{"year":2005,"finding":"In fibroblasts carrying SDHA type I mutations, SDH deficiency leads to succinate accumulation and HIF-1alpha nuclear translocation under normoxic conditions (pseudo-hypoxia). This translocation is independent of superoxide production and cellular iron availability but is inhibited by alpha-ketoglutarate, indicating that the succinate/alpha-KG ratio controls HIF-1alpha prolyl hydroxylase activity in SDH-deficient cells.","method":"Cell-based assays in SDHA-mutant fibroblasts, HIF-1alpha nuclear translocation assay, alpha-KG supplementation rescue experiments","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal mechanistic experiments (succinate measurement, HIF-1alpha localization, pharmacological rescue with alpha-KG, ROS independence confirmed), replicated in subsequent studies","pmids":["16195397"],"is_preprint":false},{"year":2010,"finding":"A germline SDHA mutation (p.Arg589Trp) causes loss of SDH enzymatic activity in tumor tissue and in a yeast model, and results in pseudo-hypoxia with increased HIF-1alpha and angiogenesis (CD34 upregulation), establishing SDHA as a tumor suppressor gene whose loss-of-function mimics hypoxia via succinate accumulation.","method":"Immunohistochemistry, yeast complementation model, in vitro enzymatic activity assay, microarray transcriptome analysis, LOH analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (IHC, yeast functional model, enzymatic assay, transcriptomics) in a single study; replicated by multiple subsequent labs","pmids":["20484225"],"is_preprint":false},{"year":2007,"finding":"Proximal inhibition of complex II at SDHA (by RNA interference or pharmacological inhibition) does not increase normoxic ROS production or HIF-alpha stabilization and results in decreased cell growth in vitro and in vivo, in contrast to distal subunit (SdhB) inhibition which increases ROS and HIF-alpha. This distinguishes the mechanism of SDHA loss-of-function from that of SDHB/C/D mutations.","method":"RNA interference knockdown, pharmacological complex II inhibition, ROS measurement, HIF-alpha stabilization assay, in vitro and in vivo growth assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal RNAi knockdown of multiple subunits with ROS and HIF readouts, both in vitro and in vivo, in single rigorous study","pmids":["17967865"],"is_preprint":false},{"year":2008,"finding":"Nuclear respiratory factor-1 (NRF-1) binds the promoters of SDHa and SDHd (but not SDHB or SDHC) and transcriptionally regulates Complex II expression. NRF-1 silencing specifically decreases SDHa expression, inactivates Complex II, and leads to aerobic HIF-1alpha stabilization and nuclear translocation in cardiomyocytes; this is reversible by high alpha-ketoglutarate concentrations and independent of mitochondrial ROS.","method":"Promoter analysis, gene silencing (NRF-1 and SDHa), chromatin immunoprecipitation (ChIP), HIF-1alpha localization assay, succinate oxidation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP confirming NRF-1 binding to SDHa promoter, combined with gene silencing and functional HIF-1alpha readout; multiple orthogonal methods in single study","pmids":["18252725"],"is_preprint":false},{"year":2014,"finding":"The assembly factor SDH5/SDHAF2 is protected from LON protease (LONM)-mediated degradation in mitochondria through its stable interaction with SDHA. SDH5(G78R), a paraganglioma-causing mutation, fails to form a stable complex with SDHA and is rapidly degraded by LONM, establishing that SDHA binding is required to stabilize SDHAF2 from proteolytic turnover.","method":"Import-chase analysis in isolated human mitochondria, in vitro LON degradation assay, Blue Native PAGE, LONM depletion experiments","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in organello and in vitro reconstitution of SDHA-SDHAF2 interaction and LON-mediated degradation, multiple orthogonal methods in single study","pmids":["24414418"],"is_preprint":false},{"year":2019,"finding":"SIRT5 desuccinylates SDHA at lysine K547; this desuccinylation by mimetic mutation (K547R) suppresses SDHA enzymatic activity through inhibition of SDH5/SDHAF2 binding, promoting ccRCC cell proliferation. SIRT5 silencing leads to hypersuccinylation and reactivation of SDHA, confirming SIRT5 as the desuccinylase for SDHA at K547.","method":"Tandem mass tag labeling/LC-MS/MS succinylome profiling, site-directed mutagenesis (K547R), Co-IP, SDHA enzymatic activity assay, cell proliferation assay, SIRT5 knockdown","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spec identification of succinylation site plus mutagenesis, Co-IP, and functional enzyme activity assay; single lab","pmids":["30703481"],"is_preprint":false},{"year":2023,"finding":"SIRT3-mediated deacetylation of SDHA activates mitochondrial complex II activity and ATP production; in rotenone-induced PD models, SIRT3 activity is suppressed, leading to SDHA hyperacetylation and impaired complex II activity. Activation of SIRT3 (by icariin or honokiol) or overexpression of SDHA rescues complex II activity and protects neurons from rotenone-induced damage.","method":"In vivo rat PD model, in vitro MN9D cell model, SIRT3 activation/inhibition, SDHA overexpression, complex II activity assay, ATP measurement, Western blot for acetylated SDHA","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity assay plus post-translational modification readout plus genetic rescue; single lab, two model systems","pmids":["38087172"],"is_preprint":false},{"year":2022,"finding":"SDHA/B reduction in HCC leads to succinate accumulation, which facilitates deNEDDylation of cullin1, disrupting the SCF β-TrCP E3 ubiquitin ligase complex, and consequently stabilizing and activating YAP/TAZ. Accelerated cell proliferation and tumor growth caused by SDHA/B depletion or succinate exposure are largely dependent on aberrant YAP/TAZ activation.","method":"RNA sequencing, SDHA/B depletion, succinate exposure, Western blot for YAP/TAZ and cullin1 NEDDylation, co-immunoprecipitation, in vitro proliferation and in vivo tumor growth assays","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway established with Co-IP, cullin NEDDylation assay, and rescue experiments; single lab","pmids":["35713976"],"is_preprint":false},{"year":2019,"finding":"SDHA gain-of-function germline mutations in patients with persistent polyclonal B cell lymphocytosis (PPBL) lead to accumulation of fumarate in B cells, which engages the KEAP1-Nrf2 system to drive transcription of inflammatory cytokine genes, constituting pathological mitochondrial retrograde signaling.","method":"Exome sequencing, extracellular acidification/oxygen consumption rate measurement, metabolite profiling (fumarate), Nrf2 target gene expression analysis, in vivo IL-6 blockade trial","journal":"Nature immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional metabolomic and transcriptional readouts in patient-derived B cells combined with in vivo therapeutic intervention; single study, multiple methods","pmids":["31527833"],"is_preprint":false},{"year":2016,"finding":"MicroRNA-31 (miR-31) suppresses SDHA expression, vital for mitochondrial electron transport chain complex II; miR-31 overexpression lowers SDHA expression and oxygen consumption rates in partially reprogrammed iPSCs, and co-transduction with Yamanaka factors results in a 2.7-fold increase in full reprogramming, establishing a miR-31/SDHA axis that regulates metabolic switching during reprogramming.","method":"miR-31 overexpression, SDHA expression measurement, oxygen consumption rate (Seahorse), iPSC reprogramming efficiency assay (TRA1-60 staining)","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct miRNA overexpression with functional metabolic and reprogramming readouts; single lab, multiple methods","pmids":["27346679"],"is_preprint":false},{"year":2023,"finding":"Flavin adenine dinucleotide (FAD) covalently bound to SDHA (flavinated SDHA) is responsible for autofluorescence changes in the FAD spectral region in oral squamous cell carcinoma cells; lower levels of flavinated SDHA in OSCC cells result in decreased SDHB levels (since flavinated SDHA is required for functional complexation with SDHB) and altered cellular metabolism.","method":"Autofluorescence spectroscopy, SDHA/SDHB protein quantification, metabolic profiling, cell-based assays","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct measurement of FAD-SDHA autofluorescence and SDHB co-complex dependency; single lab, multiple methods","pmids":["37945749"],"is_preprint":false},{"year":2025,"finding":"HINT3 interacts with SDHA and suppresses HDAC1 expression, preventing SDHA deacetylation at K335; this reduces SDH activity and mitochondrial ROS production during cardiac ischemia-reperfusion injury. Cardiomyocyte-specific HINT3 knockout exacerbates myocardial injury and mitochondrial dysfunction, while HINT3 overexpression is protective, establishing the HINT3-HDAC1-SDHA axis in mitochondrial regulation.","method":"Mouse cardiac I/R model, cardiomyocyte-specific knockout and overexpression, Co-IP (HINT3-SDHA interaction), HDAC1 expression measurement, SDHA acetylation at K335 assay, SDH activity assay, mitochondrial ROS measurement","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing HINT3-SDHA interaction, site-specific acetylation (K335), SDH activity readout, genetic KO/OE with defined phenotype; single lab","pmids":["40755357"],"is_preprint":false},{"year":2023,"finding":"CAV1 (Caveolin-1) directly binds SDHA and triggers its ubiquitination and proteasomal degradation, leading to mitochondrial dysfunction and apoptosis in cardiomyocytes under palmitate conditions; silencing CAV1 reduces apoptosis and improves mitochondrial function in a manner blocked by SDHA knockdown.","method":"Co-IP (CAV1-SDHA interaction), ubiquitination assay, CAV1 silencing/overexpression, SDHA knockdown, cell viability and apoptosis assays, mitochondrial function assays, in vivo db/db mouse model","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, epistasis via double knockdown; single lab","pmids":["37804808"],"is_preprint":false},{"year":2025,"finding":"EPAS1 (HIF-2α) increases SDHA expression by inhibiting HDAC2 mRNA expression, thereby increasing acetylation at the SDHA histone H3K27 site; this EPAS1-HDAC2-SDHA axis promotes TCA cycle activity and suppresses glycolysis, inhibiting proliferation and invasion of multiple myeloma cells in vitro and in vivo.","method":"EPAS1 overexpression/knockdown, HDAC2 modulation, ChIP for H3K27 acetylation at SDHA locus, SDHA expression assay, metabolic flux (TCA vs glycolysis), in vitro and in vivo proliferation assays","journal":"NPJ precision oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement by overexpression/KD with metabolic and proliferation readouts; single lab, limited mechanistic depth in abstract","pmids":["41290982"],"is_preprint":false},{"year":2012,"finding":"SDHA mutations lead to concurrent loss of both SDHA and SDHB protein expression (demonstrated by Western blotting and immunohistochemistry in GIST patients), indicating that SDHA protein is required for stability of SDHB within the complex II holocomplex.","method":"Western blotting, immunohistochemistry, next-generation sequencing, LOH analysis","journal":"Journal of the National Cancer Institute","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — consistently replicated across multiple independent cohort studies (PMIDs 21505157, 22974104, 23612575) demonstrating SDHA loss leads to SDHB loss","pmids":["21505157","22974104","23612575"],"is_preprint":false},{"year":2024,"finding":"Using an SDHA-knockout cell line with Bxb1-mediated variant reintroduction, cancer-associated SDHA missense variants can be distinguished from non-cancer variants by the degree of SDH enzymatic dysfunction they cause; SDH activity data predict cancer pathogenicity with performance exceeding computational tools, providing a functional assay for clinical variant classification.","method":"SDHA-knockout cell line, Bxb1-mediated recombination for variant introduction, SDH activity assay, logistic regression for pathogenicity prediction","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — direct enzymatic activity measurement in defined cell model for 72 variants; single lab, rigorous design","pmids":["39321216"],"is_preprint":false},{"year":2014,"finding":"SDHA splicing mutations (c.64-2A>G and c.1065-3C>A) result in loss of SDHA protein expression; the missense mutation c.565T>G severely affects SDHA enzymatic activity. Pathogenicity of c.565T>G was confirmed by lentiviral complementation experiments in patient fibroblasts.","method":"mRNA splicing analysis, protein expression (Western blot), enzymatic activity assay, lentiviral complementation in patient fibroblasts","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lentiviral complementation confirming loss of function, enzymatic activity assay; single lab, multiple methods","pmids":["24781757"],"is_preprint":false},{"year":2012,"finding":"Recessive SDHA mutations cause isolated complex II deficiency; Western blotting and BN-PAGE studies confirmed decreased steady-state levels of SDH subunits and impaired complex II assembly in patient-derived samples with compound heterozygous SDHA mutations.","method":"Western blot, BN-PAGE (Blue Native PAGE), biochemical complex II activity measurement, yeast complementation","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BN-PAGE assembly analysis plus enzymatic activity in patient-derived fibroblasts; single lab, multiple orthogonal methods","pmids":["22972948"],"is_preprint":false},{"year":2025,"finding":"Compound heterozygous SDHA variants (p.R512Q and p.R585W) cause significant decreases in SDH activity, SDH subunit levels, and impaired complex II assembly in patient-derived fibroblasts; additionally, complex I activity and CI-containing supercomplex formation were impaired, though basal and maximal respiration rates remained unchanged while spare respiratory capacity was significantly reduced.","method":"Patient-derived fibroblast analysis, SDH enzymatic activity assay, BN-PAGE for assembly, complex I activity assay, Seahorse respirometry","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple enzymatic and assembly assays in patient-derived cells; single lab","pmids":["41833598"],"is_preprint":false},{"year":2025,"finding":"Yeast Saccharomyces cerevisiae complementation assays demonstrated that biallelic SDHA mutations found in a pediatric patient with seizures and behavioral dysregulation are functionally deleterious to mitochondrial complex II function.","method":"Yeast complementation assay, mitochondrial respiratory chain activity measurement, muscle biopsy biochemistry","journal":"Clinical genetics","confidence":"Low","confidence_rationale":"Tier 2 / Weak — yeast complementation as functional validation; single case study, single lab","pmids":["40045913"],"is_preprint":false},{"year":2021,"finding":"A heterozygous de novo SDHA variant (p.Arg662Cys) causes considerably decreased complex II residual activity in patient-derived fibroblasts and lymphocytes. Protein modeling suggests this substitution compromises FAD-binding to SDHA at the C-terminus, impairing FAD binding and decreasing entire complex II activity.","method":"Complex II enzymatic activity assay in patient fibroblasts and lymphocytes, protein structural modeling","journal":"Metabolic brain disease","confidence":"Low","confidence_rationale":"Tier 2–3 / Weak — enzymatic activity in patient cells plus computational structural prediction; single case, single lab","pmids":["33471299"],"is_preprint":false}],"current_model":"SDHA encodes the catalytic flavoprotein subunit of mitochondrial complex II (succinate dehydrogenase), where it covalently binds FAD (flavination facilitated by assembly factor SDHAF2 and a dicarboxylate cofactor that repositions the active site and adjusts pKa of R451) to oxidize succinate to fumarate; loss of SDHA enzymatic activity causes succinate accumulation that inhibits HIF prolyl hydroxylases, driving pseudo-hypoxic HIF-1alpha stabilization and tumor suppressor phenotypes, while SDHA activity is post-translationally regulated by SIRT3-mediated deacetylation (activating) and SIRT5-mediated desuccinylation at K547 (inhibitory), CAV1-mediated ubiquitin-proteasomal degradation, and HINT3/HDAC1-controlled acetylation at K335; SDHA protein also stabilizes its assembly factor SDHAF2 from LON protease degradation, and its loss destabilizes SDHB within the mature complex."},"narrative":{"mechanistic_narrative":"SDHA encodes the catalytic flavoprotein subunit of mitochondrial complex II (succinate dehydrogenase), whose enzymatic activity oxidizes succinate to fumarate and links the TCA cycle to the electron transport chain [PMID:16195397, PMID:22972948]. Maturation of SDHA requires covalent flavination: structural and biochemical reconstitution show that the dedicated assembly factor SDHAF2, acting in synergy with a small-molecule dicarboxylate cofactor, reorients the flavin and capping domains and adjusts the pKa of R451 to support covalent FAD attachment [PMID:32887801], and flavinated SDHA is in turn required for productive complexation with and stabilization of SDHB [PMID:37945749, PMID:21505157, PMID:22974104, PMID:23612575]. SDHA loss-of-function abolishes complex II assembly and activity, causing succinate accumulation that inhibits HIF prolyl hydroxylases and drives normoxic (pseudo-hypoxic) HIF-1alpha stabilization in a manner controlled by the succinate/alpha-ketoglutarate ratio and independent of ROS and iron availability [PMID:16195397, PMID:20484225]; this establishes SDHA as a tumor suppressor whose biallelic or splicing/missense mutations cause isolated complex II deficiency and disease [PMID:20484225, PMID:24781757, PMID:22972948]. Notably, proximal inhibition at SDHA differs mechanistically from distal SDHB/C/D loss, failing to elevate ROS and instead reducing cell growth [PMID:17967865], and accumulated metabolites can act through additional effectors including YAP/TAZ stabilization via cullin1 deNEDDylation [PMID:35713976] and fumarate-driven KEAP1-Nrf2 inflammatory signaling [PMID:31527833]. SDHA expression and activity are tightly regulated: NRF-1 transcriptionally controls SDHA promoter activity [PMID:18252725], and the protein is post-translationally tuned by SIRT5-mediated desuccinylation at K547 (inhibitory, via disruption of SDHAF2 binding) [PMID:30703481], SIRT3-mediated deacetylation (activating) [PMID:38087172], HINT3/HDAC1-controlled acetylation at K335 [PMID:40755357], and CAV1-mediated ubiquitin-proteasomal degradation [PMID:37804808]. Reciprocally, SDHA binding protects its assembly factor SDHAF2 from LON protease degradation [PMID:24414418].","teleology":[{"year":2005,"claim":"Established the central mechanism by which SDHA loss causes disease: that SDH deficiency raises succinate and stabilizes HIF-1alpha under normoxia, distinguishing this from ROS- or iron-dependent routes.","evidence":"Cell-based assays in SDHA-mutant fibroblasts with HIF-1alpha localization and alpha-KG rescue","pmids":["16195397"],"confidence":"High","gaps":["Did not resolve which prolyl hydroxylase isoform is rate-limiting","Did not establish in vivo tumorigenic consequences"]},{"year":2007,"claim":"Distinguished the mechanism of SDHA (proximal) loss from SDHB/C/D (distal) loss, showing SDHA knockdown does not elevate ROS or HIF-alpha and instead reduces growth.","evidence":"Reciprocal RNAi of complex II subunits with ROS, HIF, and growth readouts in vitro and in vivo","pmids":["17967865"],"confidence":"High","gaps":["Apparent contradiction with later HIF-1alpha stabilization findings in SDHA-mutant cells not fully reconciled","Molecular basis of differential ROS production between subunits unresolved"]},{"year":2008,"claim":"Identified transcriptional control of SDHA, showing NRF-1 binds the SDHa promoter and regulates complex II expression with downstream HIF-1alpha consequences.","evidence":"Promoter analysis, ChIP, NRF-1/SDHa silencing, and HIF-1alpha localization in cardiomyocytes","pmids":["18252725"],"confidence":"High","gaps":["Co-regulators at the SDHa promoter not defined","Tissue specificity of NRF-1 control not established"]},{"year":2010,"claim":"Formally established SDHA as a tumor suppressor by tying a germline mutation to loss of enzymatic activity, pseudo-hypoxia, and angiogenesis.","evidence":"IHC, yeast complementation, enzyme assay, transcriptomics and LOH on a p.Arg589Trp tumor","pmids":["20484225"],"confidence":"High","gaps":["Single mutation studied","Tissue-specific penetrance of SDHA tumorigenesis not addressed"]},{"year":2012,"claim":"Showed that SDHA protein is required for SDHB stability and complex II assembly, providing a structural rationale for combined subunit loss in patients.","evidence":"Western blot, IHC, BN-PAGE, and yeast complementation in GIST and complex II-deficient patient samples","pmids":["21505157","22974104","23612575","22972948"],"confidence":"Medium","gaps":["Did not define the stoichiometric/structural basis of SDHB destabilization","Whether residual SDHA fragments retain partial function unclear"]},{"year":2014,"claim":"Revealed a reciprocal stabilization mechanism: SDHA binding protects assembly factor SDHAF2 from LON protease degradation, and a paraganglioma mutation breaks this interaction.","evidence":"Import-chase in isolated mitochondria, in vitro LON degradation assay, BN-PAGE, and LONM depletion","pmids":["24414418"],"confidence":"High","gaps":["Quantitative contribution of this stabilization to flavination kinetics not measured","Other proteases not excluded"]},{"year":2019,"claim":"Defined post-translational regulation of SDHA activity, showing SIRT5 desuccinylates K547 to suppress activity by impairing SDHAF2 binding.","evidence":"Succinylome MS, K547R mutagenesis, Co-IP, enzyme activity assays, and SIRT5 knockdown in ccRCC cells","pmids":["30703481"],"confidence":"Medium","gaps":["Single lab","Stoichiometry of endogenous K547 succinylation in normal tissue not quantified"]},{"year":2019,"claim":"Expanded SDHA pathology beyond loss-of-function by linking gain-of-function variants to fumarate accumulation and KEAP1-Nrf2 inflammatory signaling.","evidence":"Exome sequencing, respirometry, fumarate metabolite profiling, Nrf2 target analysis, and in vivo IL-6 blockade in PPBL patients","pmids":["31527833"],"confidence":"Medium","gaps":["Molecular basis of how variants produce gain-of-function unclear","Single patient cohort"]},{"year":2020,"claim":"Solved how SDHA acquires its FAD cofactor: a structure showing SDHAF2 plus a dicarboxylate cofactor reorient the flavin/capping domains and tune R451 pKa for covalent flavination.","evidence":"X-ray crystallography of the SDHA-SDHAF2 complex with biochemical reconstitution and mutagenesis","pmids":["32887801"],"confidence":"High","gaps":["Order of flavination relative to SDHB incorporation in vivo not fully resolved","Identity/source of the physiological dicarboxylate not established"]},{"year":2022,"claim":"Identified a HIF-independent oncogenic route, in which SDHA/B loss-derived succinate deNEDDylates cullin1 to stabilize YAP/TAZ.","evidence":"RNA-seq, depletion/succinate exposure, NEDDylation and Co-IP assays, and tumor growth assays in HCC","pmids":["35713976"],"confidence":"Medium","gaps":["Direct succinate target on the deNEDDylation machinery not identified","Single lab"]},{"year":2023,"claim":"Showed SIRT3 deacetylation activates complex II and is protective, linking SDHA acetylation status to neuronal injury.","evidence":"Rotenone PD rat/MN9D models with SIRT3 modulation, SDHA overexpression, activity and acetylation readouts","pmids":["38087172"],"confidence":"Medium","gaps":["Specific acetylated lysines not mapped","Direct vs indirect SIRT3-SDHA action not distinguished"]},{"year":2023,"claim":"Demonstrated CAV1 directly binds SDHA and drives its ubiquitin-proteasomal degradation, coupling lipotoxic stress to mitochondrial dysfunction.","evidence":"Reciprocal Co-IP, ubiquitination assay, CAV1/SDHA epistasis knockdowns, and db/db mouse model","pmids":["37804808"],"confidence":"Medium","gaps":["E3 ligase mediating CAV1-dependent SDHA ubiquitination not identified","Single lab"]},{"year":2023,"claim":"Connected SDHA flavination state to SDHB levels and cellular metabolism, showing low flavinated SDHA reduces SDHB in cancer cells.","evidence":"Autofluorescence spectroscopy, SDHA/SDHB quantification, and metabolic profiling in OSCC cells","pmids":["37945749"],"confidence":"Medium","gaps":["Cause of reduced flavination in OSCC not defined","Single lab"]},{"year":2024,"claim":"Translated mechanistic knowledge into a functional pathogenicity classifier, scoring SDHA missense variants by enzymatic dysfunction.","evidence":"SDHA-knockout cell line with Bxb1 variant reintroduction and SDH activity-based logistic regression on 72 variants","pmids":["39321216"],"confidence":"Medium","gaps":["Does not capture non-enzymatic (e.g. gain-of-function or assembly) variant effects","Single lab assay"]},{"year":2025,"claim":"Added an acetylation-control axis, with HINT3 suppressing HDAC1 to maintain SDHA K335 acetylation and restrain SDH activity and ROS in cardiac ischemia-reperfusion.","evidence":"Cardiac I/R mouse model with cardiomyocyte HINT3 KO/OE, Co-IP, K335 acetylation, and SDH activity assays","pmids":["40755357"],"confidence":"Medium","gaps":["Direct vs indirect HINT3-HDAC1-SDHA wiring not fully dissected","Single lab"]},{"year":null,"claim":"How the multiple, sometimes opposing regulatory inputs on SDHA (acetylation, succinylation, ubiquitination, transcription) are integrated in a given tissue and reconciled with the divergent ROS/HIF outcomes of proximal versus distal complex II loss remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model integrating PTM crosstalk on SDHA","Tissue-specific dominance of each regulator undetermined","Quantitative relationship between flavination, assembly, and downstream succinate signaling not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,2,3,16,18]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5,7,12,18]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2,8,9,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,9,15,16,18]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,2,9]}],"complexes":["mitochondrial complex II (succinate dehydrogenase)"],"partners":["SDHAF2","SDHB","SIRT5","SIRT3","HINT3","CAV1","LONP1","NRF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P31040","full_name":"Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial","aliases":["Flavoprotein subunit of complex II","Fp","Malate dehydrogenase [quinone] flavoprotein subunit"],"length_aa":664,"mass_kda":72.7,"function":"Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q) (PubMed:10746566, PubMed:24781757). SDH also oxidizes malate to the non-canonical enol form of oxaloacetate, enol-oxaloacetate (By similarity). Enol-oxaloacetate, which is a potent inhibitor of the succinate dehydrogenase activity, is further isomerized into keto-oxaloacetate (By similarity). Can act as a tumor suppressor (PubMed:20484225)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/P31040/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SDHA","classification":"Not Classified","n_dependent_lines":338,"n_total_lines":1208,"dependency_fraction":0.27980132450331124},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ASS1","stoichiometry":0.2},{"gene":"KIF2C","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SDHA","total_profiled":1310},"omim":[{"mim_id":"619259","title":"NEURODEGENERATION WITH ATAXIA AND LATE-ONSET OPTIC ATROPHY; NDAXOA","url":"https://www.omim.org/entry/619259"},{"mim_id":"619224","title":"MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 4; MC2DN4","url":"https://www.omim.org/entry/619224"},{"mim_id":"619198","title":"SUCCINATE DEHYDROGENASE COMPLEX ASSEMBLY FACTOR 4; SDHAF4","url":"https://www.omim.org/entry/619198"},{"mim_id":"618855","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 44; COXPD44","url":"https://www.omim.org/entry/618855"},{"mim_id":"617710","title":"NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH OR WITHOUT SEIZURES; NEMMLAS","url":"https://www.omim.org/entry/617710"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":522.4},{"tissue":"skeletal muscle","ntpm":446.5}],"url":"https://www.proteinatlas.org/search/SDHA"},"hgnc":{"alias_symbol":["FP","SDHF"],"prev_symbol":["SDH2"]},"alphafold":{"accession":"P31040","domains":[{"cath_id":"3.90.700.10","chopping":"297-406","consensus_level":"medium","plddt":98.1739,"start":297,"end":406}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P31040","model_url":"https://alphafold.ebi.ac.uk/files/AF-P31040-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P31040-F1-predicted_aligned_error_v6.png","plddt_mean":93.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SDHA","jax_strain_url":"https://www.jax.org/strain/search?query=SDHA"},"sequence":{"accession":"P31040","fasta_url":"https://rest.uniprot.org/uniprotkb/P31040.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P31040/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P31040"}},"corpus_meta":[{"pmid":"20484225","id":"PMC_20484225","title":"SDHA is a tumor suppressor gene causing paraganglioma.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20484225","citation_count":535,"is_preprint":false},{"pmid":"17967865","id":"PMC_17967865","title":"Loss of the SdhB, but Not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17967865","citation_count":364,"is_preprint":false},{"pmid":"21752896","id":"PMC_21752896","title":"SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas.","date":"2011","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/21752896","citation_count":228,"is_preprint":false},{"pmid":"25720320","id":"PMC_25720320","title":"SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T).","date":"2015","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/25720320","citation_count":177,"is_preprint":false},{"pmid":"22308473","id":"PMC_22308473","title":"The protein SdhA maintains the integrity of the Legionella-containing vacuole.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22308473","citation_count":158,"is_preprint":false},{"pmid":"28384794","id":"PMC_28384794","title":"Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.","date":"2017","source":"JAMA oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28384794","citation_count":152,"is_preprint":false},{"pmid":"23282968","id":"PMC_23282968","title":"Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation.","date":"2013","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23282968","citation_count":141,"is_preprint":false},{"pmid":"21505157","id":"PMC_21505157","title":"SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing.","date":"2011","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/21505157","citation_count":120,"is_preprint":false},{"pmid":"16195397","id":"PMC_16195397","title":"Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions.","date":"2005","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16195397","citation_count":120,"is_preprint":false},{"pmid":"22955521","id":"PMC_22955521","title":"Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors.","date":"2012","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/22955521","citation_count":100,"is_preprint":false},{"pmid":"16361598","id":"PMC_16361598","title":"Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA).","date":"2006","source":"Journal of neurology, neurosurgery, and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/16361598","citation_count":99,"is_preprint":false},{"pmid":"22972948","id":"PMC_22972948","title":"Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency.","date":"2012","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22972948","citation_count":96,"is_preprint":false},{"pmid":"30703481","id":"PMC_30703481","title":"SIRT5-mediated SDHA desuccinylation promotes clear cell renal cell carcinoma tumorigenesis.","date":"2019","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30703481","citation_count":94,"is_preprint":false},{"pmid":"23060355","id":"PMC_23060355","title":"Loss of SDHA expression identifies SDHA mutations in succinate dehydrogenase-deficient gastrointestinal stromal tumors.","date":"2013","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23060355","citation_count":91,"is_preprint":false},{"pmid":"17351036","id":"PMC_17351036","title":"A novel fur- and iron-regulated small RNA, NrrF, is required for indirect fur-mediated regulation of the sdhA and sdhC genes in Neisseria meningitidis.","date":"2007","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/17351036","citation_count":91,"is_preprint":false},{"pmid":"23612575","id":"PMC_23612575","title":"Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST.","date":"2013","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/23612575","citation_count":88,"is_preprint":false},{"pmid":"23633203","id":"PMC_23633203","title":"Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma.","date":"2013","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23633203","citation_count":86,"is_preprint":false},{"pmid":"24781757","id":"PMC_24781757","title":"SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors.","date":"2014","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/24781757","citation_count":78,"is_preprint":false},{"pmid":"23174939","id":"PMC_23174939","title":"SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors.","date":"2012","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/23174939","citation_count":65,"is_preprint":false},{"pmid":"29177515","id":"PMC_29177515","title":"Clinical Aspects of SDHA-Related Pheochromocytoma and Paraganglioma: A Nationwide Study.","date":"2018","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/29177515","citation_count":63,"is_preprint":false},{"pmid":"31299266","id":"PMC_31299266","title":"Incidence of succinate dehydrogenase and fumarate hydratase-deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC.","date":"2019","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31299266","citation_count":60,"is_preprint":false},{"pmid":"23109135","id":"PMC_23109135","title":"Overexpression of insulin-like growth factor 1 receptor and frequent mutational inactivation of SDHA in wild-type SDHB-negative gastrointestinal stromal tumors.","date":"2012","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23109135","citation_count":60,"is_preprint":false},{"pmid":"25724004","id":"PMC_25724004","title":"A Novel SDHA-deficient Renal Cell Carcinoma Revealed by Comprehensive Genomic Profiling.","date":"2015","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25724004","citation_count":55,"is_preprint":false},{"pmid":"22974104","id":"PMC_22974104","title":"SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors.","date":"2012","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22974104","citation_count":53,"is_preprint":false},{"pmid":"30854332","id":"PMC_30854332","title":"Clinical, Diagnostic, and Treatment Characteristics of SDHA-Related Metastatic Pheochromocytoma and Paraganglioma.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30854332","citation_count":50,"is_preprint":false},{"pmid":"31527833","id":"PMC_31527833","title":"SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2.","date":"2019","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31527833","citation_count":47,"is_preprint":false},{"pmid":"28546994","id":"PMC_28546994","title":"SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity.","date":"2017","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28546994","citation_count":43,"is_preprint":false},{"pmid":"31596927","id":"PMC_31596927","title":"Elevated Endogenous SDHA Drives Pathological Metabolism in Highly Metastatic Uveal Melanoma.","date":"2019","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/31596927","citation_count":43,"is_preprint":false},{"pmid":"18252725","id":"PMC_18252725","title":"Transcriptional Regulation of SDHa flavoprotein by nuclear respiratory factor-1 prevents pseudo-hypoxia in aerobic cardiac cells.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18252725","citation_count":43,"is_preprint":false},{"pmid":"30068732","id":"PMC_30068732","title":"Germline SDHA mutations in children and adults with cancer.","date":"2018","source":"Cold Spring Harbor molecular case studies","url":"https://pubmed.ncbi.nlm.nih.gov/30068732","citation_count":38,"is_preprint":false},{"pmid":"32887801","id":"PMC_32887801","title":"The roles of SDHAF2 and dicarboxylate in covalent flavinylation of SDHA, the human complex II flavoprotein.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32887801","citation_count":38,"is_preprint":false},{"pmid":"23649096","id":"PMC_23649096","title":"The Dot/Icm effector SdhA is necessary for virulence of Legionella pneumophila in Galleria mellonella and A/J mice.","date":"2013","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/23649096","citation_count":38,"is_preprint":false},{"pmid":"24414418","id":"PMC_24414418","title":"Mitochondrial matrix proteostasis is linked to hereditary paraganglioma: LON-mediated turnover of the human flavinylation factor SDH5 is regulated by its interaction with SDHA.","date":"2014","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/24414418","citation_count":38,"is_preprint":false},{"pmid":"27346679","id":"PMC_27346679","title":"MiR-31/SDHA Axis Regulates Reprogramming Efficiency through Mitochondrial Metabolism.","date":"2016","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27346679","citation_count":37,"is_preprint":false},{"pmid":"26722403","id":"PMC_26722403","title":"A novel germline mutation in SDHA identified in a rare case of gastrointestinal stromal tumor complicated with renal cell carcinoma.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26722403","citation_count":36,"is_preprint":false},{"pmid":"27683074","id":"PMC_27683074","title":"SDHA mutation with dominant transmission results in complex II deficiency with ocular, cardiac, and neurologic involvement.","date":"2016","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/27683074","citation_count":35,"is_preprint":false},{"pmid":"17376234","id":"PMC_17376234","title":"Sequence variation in human succinate dehydrogenase genes: evidence for long-term balancing selection on SDHA.","date":"2007","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/17376234","citation_count":34,"is_preprint":false},{"pmid":"22245674","id":"PMC_22245674","title":"Sorbitol dehydrogenase of Aspergillus niger, SdhA, is part of the oxido-reductive D-galactose pathway and essential for D-sorbitol catabolism.","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/22245674","citation_count":32,"is_preprint":false},{"pmid":"32843629","id":"PMC_32843629","title":"Cryo-EM structure of trimeric Mycobacterium smegmatis succinate dehydrogenase with a membrane-anchor SdhF.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32843629","citation_count":31,"is_preprint":false},{"pmid":"2987185","id":"PMC_2987185","title":"Cloning and expression in Escherichia coli of sdhA, the structural gene for cytochrome b558 of the Bacillus subtilis succinate dehydrogenase complex.","date":"1985","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/2987185","citation_count":30,"is_preprint":false},{"pmid":"35713976","id":"PMC_35713976","title":"SDHA/B reduction promotes hepatocellular carcinoma by facilitating the deNEDDylation of cullin1 and stabilizing YAP/TAZ.","date":"2022","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/35713976","citation_count":29,"is_preprint":false},{"pmid":"29978154","id":"PMC_29978154","title":"Pathogenicity and Penetrance of Germline SDHA Variants in Pheochromocytoma and Paraganglioma (PPGL).","date":"2018","source":"Journal of the Endocrine Society","url":"https://pubmed.ncbi.nlm.nih.gov/29978154","citation_count":29,"is_preprint":false},{"pmid":"19422848","id":"PMC_19422848","title":"Subchronic exposure to arsenic decreased Sdha expression in the brain of mice.","date":"2009","source":"Neurotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/19422848","citation_count":29,"is_preprint":false},{"pmid":"10779596","id":"PMC_10779596","title":"Succinate dehydrogenase in Plasmodium falciparum mitochondria: molecular characterization of the SDHA and SDHB genes for the catalytic subunits, the flavoprotein (Fp) and iron-sulfur (Ip) subunits.","date":"2000","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/10779596","citation_count":29,"is_preprint":false},{"pmid":"36291881","id":"PMC_36291881","title":"Upregulation of Succinate Dehydrogenase (SDHA) Contributes to Enhanced Bioenergetics of Ovarian Cancer Cells and Higher Sensitivity to Anti-Metabolic Agent Shikonin.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36291881","citation_count":23,"is_preprint":false},{"pmid":"3934334","id":"PMC_3934334","title":"Cloning and deletion analysis of a genomic segment of Bacillus subtilis coding for the sdhA, B, C (succinate dehydrogenase) and gerE (spore germination) loci.","date":"1985","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/3934334","citation_count":21,"is_preprint":false},{"pmid":"34731604","id":"PMC_34731604","title":"SdhA blocks disruption of the Legionella-containing vacuole by hijacking the OCRL phosphatase.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34731604","citation_count":20,"is_preprint":false},{"pmid":"38087172","id":"PMC_38087172","title":"SIRT3-Mediated Deacetylation of SDHA Rescues Mitochondrial Bioenergetics Contributing to Neuroprotection in Rotenone-Induced PD Models.","date":"2023","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/38087172","citation_count":20,"is_preprint":false},{"pmid":"39133175","id":"PMC_39133175","title":"SDHA-related phaeochromocytoma and paraganglioma: review and clinical management.","date":"2024","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39133175","citation_count":15,"is_preprint":false},{"pmid":"36980917","id":"PMC_36980917","title":"SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/36980917","citation_count":15,"is_preprint":false},{"pmid":"37804808","id":"PMC_37804808","title":"Lentinan alleviates diabetic cardiomyopathy by suppressing CAV1/SDHA-regulated mitochondrial dysfunction.","date":"2023","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/37804808","citation_count":15,"is_preprint":false},{"pmid":"37326247","id":"PMC_37326247","title":"The MADS-box protein SlTAGL1 regulates a ripening-associated SlDQD/SDH2 involved in flavonoid biosynthesis and resistance against Botrytis cinerea in post-harvest tomato fruit.","date":"2023","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/37326247","citation_count":13,"is_preprint":false},{"pmid":"35059314","id":"PMC_35059314","title":"SDHA Germline Variants in Adult Patients With SDHA-Mutant Gastrointestinal Stromal Tumor.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35059314","citation_count":12,"is_preprint":false},{"pmid":"10799306","id":"PMC_10799306","title":"The nuclear-encoded SDH2-RPS14 precursor is proteolytically processed between SDH2 and RPS14 to generate maize mitochondrial RPS14.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10799306","citation_count":11,"is_preprint":false},{"pmid":"36829855","id":"PMC_36829855","title":"Ginsenoside Rg1 Delays Chronological Aging in a Yeast Model via CDC19- and SDH2-Mediated Cellular Metabolism.","date":"2023","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36829855","citation_count":11,"is_preprint":false},{"pmid":"33375756","id":"PMC_33375756","title":"LPS1, Encoding Iron-Sulfur Subunit SDH2-1 of Succinate Dehydrogenase, Affects Leaf Senescence and Grain Yield in Rice.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33375756","citation_count":11,"is_preprint":false},{"pmid":"29850869","id":"PMC_29850869","title":"Sdha+/- Rats Display Minimal Muscle Pathology Without Significant Behavioral or Biochemical Abnormalities.","date":"2018","source":"Journal of neuropathology and experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29850869","citation_count":10,"is_preprint":false},{"pmid":"36153644","id":"PMC_36153644","title":"MicroRNA-16-5p exacerbates sepsis by upregulating aerobic glycolysis via SIRT3-SDHA axis.","date":"2022","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/36153644","citation_count":10,"is_preprint":false},{"pmid":"31853292","id":"PMC_31853292","title":"Methylsulfonylmethane inhibits cortisol-induced stress through p53-mediated SDHA/HPRT1 expression in racehorse skeletal muscle cells: A primary step against exercise stress.","date":"2019","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31853292","citation_count":9,"is_preprint":false},{"pmid":"33471299","id":"PMC_33471299","title":"A novel de novo heterozygous pathogenic variant in the SDHA gene results in childhood onset bilateral optic atrophy and cognitive impairment.","date":"2021","source":"Metabolic brain disease","url":"https://pubmed.ncbi.nlm.nih.gov/33471299","citation_count":7,"is_preprint":false},{"pmid":"36232604","id":"PMC_36232604","title":"PIKE-A Modulates Mitochondrial Metabolism through Increasing SDHA Expression Mediated by STAT3/FTO Axis.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36232604","citation_count":7,"is_preprint":false},{"pmid":"22569713","id":"PMC_22569713","title":"Intraabdominal adhesion formation is associated with differential mRNA expression of metabolic genes PDHb and SDHa.","date":"2012","source":"Archives of gynecology and obstetrics","url":"https://pubmed.ncbi.nlm.nih.gov/22569713","citation_count":7,"is_preprint":false},{"pmid":"24866946","id":"PMC_24866946","title":"Corynebacterium glutamicum sdhA encoding succinate dehydrogenase subunit A plays a role in cysR-mediated sulfur metabolism.","date":"2014","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/24866946","citation_count":7,"is_preprint":false},{"pmid":"33602019","id":"PMC_33602019","title":"Upregulation of SDHA inhibited proliferation, migration, and invasion of clear cell renal cell carcinoma cells via inactivation of the Wnt/β-catenin pathway.","date":"2021","source":"Journal of receptor and signal transduction research","url":"https://pubmed.ncbi.nlm.nih.gov/33602019","citation_count":6,"is_preprint":false},{"pmid":"32534711","id":"PMC_32534711","title":"Synchronous detection of SDHA-related gallbladder paraganglioma and pancreatic neuroendocrine tumor.","date":"2020","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/32534711","citation_count":6,"is_preprint":false},{"pmid":"40755357","id":"PMC_40755357","title":"The Role of HINT3 in Myocardial Ischemia-Reperfusion Injury in Male Mice: Mechanisms Involving SDHA and its Acetylation.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40755357","citation_count":5,"is_preprint":false},{"pmid":"40119440","id":"PMC_40119440","title":"Unveiling the hidden role of SDHA in breast cancer proliferation: a novel therapeutic avenue.","date":"2025","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/40119440","citation_count":5,"is_preprint":false},{"pmid":"40832885","id":"PMC_40832885","title":"Succinate Dehydrogenase Subunit A (SDHA) Mediated Microglia Extracellular Traps Formation Participating in Cerebral Ischemic Reperfusion Injury.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40832885","citation_count":4,"is_preprint":false},{"pmid":"32957698","id":"PMC_32957698","title":"SDHB and SDHA Immunohistochemistry in Canine Pheochromocytomas.","date":"2020","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/32957698","citation_count":4,"is_preprint":false},{"pmid":"39321216","id":"PMC_39321216","title":"A Novel Human SDHA-Knockout Cell Line Model for the Functional Analysis of Clinically Relevant SDHA Variants.","date":"2024","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/39321216","citation_count":4,"is_preprint":false},{"pmid":"38770192","id":"PMC_38770192","title":"SDHA secondary findings in germline testing: counseling and surveillance considerations.","date":"2024","source":"Endocrine oncology (Bristol, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38770192","citation_count":4,"is_preprint":false},{"pmid":"31368675","id":"PMC_31368675","title":"First-positive surveillance screening in an asymptomatic SDHA germline mutation carrier.","date":"2019","source":"Endocrinology, diabetes & metabolism case reports","url":"https://pubmed.ncbi.nlm.nih.gov/31368675","citation_count":4,"is_preprint":false},{"pmid":"37679739","id":"PMC_37679739","title":"Analysis of the stability of the reference genes GAPDH, SDHA and RPL-19 in sheep from a semi-arid region infected by gastrointestinal nematodes.","date":"2023","source":"BMC veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/37679739","citation_count":4,"is_preprint":false},{"pmid":"33031286","id":"PMC_33031286","title":"Somatic SDHA mutations in paragangliomas in siblings: Case report of 2 cases.","date":"2020","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33031286","citation_count":4,"is_preprint":false},{"pmid":"32198912","id":"PMC_32198912","title":"SDHA-mediated Warburg effect in malignantly transformed human bronchial epithelial cells following long-term exposure to radon.","date":"2020","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/32198912","citation_count":4,"is_preprint":false},{"pmid":"33854214","id":"PMC_33854214","title":"Familial wild-type gastrointestinal stromal tumour in association with germline truncating variants in both SDHA and PALB2.","date":"2021","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/33854214","citation_count":4,"is_preprint":false},{"pmid":"32302684","id":"PMC_32302684","title":"CYC1, SDHA, UQCRC1, UQCRQ, and SDHB might be important biomarkers in kidney transplant rejection.","date":"2020","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32302684","citation_count":3,"is_preprint":false},{"pmid":"35875079","id":"PMC_35875079","title":"Co-occurrence of VHL and SDHA Pathogenic Variants: A Case Report.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35875079","citation_count":3,"is_preprint":false},{"pmid":"40821099","id":"PMC_40821099","title":"Exploring the critical role of SDHA in breast cancer proliferation: implications for novel therapeutic strategies.","date":"2025","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/40821099","citation_count":3,"is_preprint":false},{"pmid":"33960148","id":"PMC_33960148","title":"Progressive cerebellar atrophy in a patient with complex II and III deficiency and a novel deleterious variant in SDHA: A Counseling Conundrum.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33960148","citation_count":3,"is_preprint":false},{"pmid":"41290982","id":"PMC_41290982","title":"EPAS1 increases SDHA to inhibit proliferation of multiple myeloma cells by restoring TCA Cycle.","date":"2025","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41290982","citation_count":2,"is_preprint":false},{"pmid":"37945749","id":"PMC_37945749","title":"Flavinated SDHA underlies the change in intrinsic optical properties of oral cancers.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/37945749","citation_count":2,"is_preprint":false},{"pmid":"33839693","id":"PMC_33839693","title":"A case of Carney triad complicated by renal cell carcinoma and a germline SDHA pathogenic variant.","date":"2021","source":"Endocrinology, diabetes & metabolism case reports","url":"https://pubmed.ncbi.nlm.nih.gov/33839693","citation_count":2,"is_preprint":false},{"pmid":"35651799","id":"PMC_35651799","title":"A Novel Germline SDHA Gene Mutation and Co-Occurring Somatic KIT Activating Mutation in a Patient With Pediatric Central Nervous System Germ Cell Tumor: Case Report.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35651799","citation_count":2,"is_preprint":false},{"pmid":"40074439","id":"PMC_40074439","title":"Management succinate release through SDHA by G protein-coupled receptor 91 signal, TRAP1, and SIRT3 regulation in lung cancer cells by NAR nanoparticles.","date":"2025","source":"Journal, genetic engineering & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/40074439","citation_count":2,"is_preprint":false},{"pmid":"40141095","id":"PMC_40141095","title":"Transcriptional Expression of SLC2A3 and SDHA Predicts the Risk of Local Tumor Recurrence in Patients with Head and Neck Squamous Cell Carcinomas Treated Primarily with Radiotherapy or Chemoradiotherapy.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40141095","citation_count":1,"is_preprint":false},{"pmid":"36915446","id":"PMC_36915446","title":"An unusual paraesophageal and diaphragmatic SDHA-deficient gastrointestinal stromal tumor (GIST) metastases case report.","date":"2023","source":"Journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36915446","citation_count":1,"is_preprint":false},{"pmid":"41076213","id":"PMC_41076213","title":"Structure and expression kinetics of Piscirickettsia salmonis sdhA during infection of Atlantic salmon macrophage-like cells.","date":"2025","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41076213","citation_count":1,"is_preprint":false},{"pmid":"40045913","id":"PMC_40045913","title":"Impact of SDHA Mutations on Yeast Growth and Mitochondrial Function. Case Study Linking Genetic Findings to Clinical Phenotypes.","date":"2025","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40045913","citation_count":1,"is_preprint":false},{"pmid":"38885448","id":"PMC_38885448","title":"Combined Germline and Mosaic SDHA Mutation Is Associated With a Multicancer Syndrome Including Neuroblastoma, Renal Cancer, and Multifocal GI Tumor.","date":"2024","source":"JCO precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38885448","citation_count":1,"is_preprint":false},{"pmid":"40563592","id":"PMC_40563592","title":"The Identification of a Key Regulator of Mitochondrial Metabolism, the LRPPRC Protein, as a Novel Therapeutic Target in SDHA-Overexpressing Ovarian Tumors.","date":"2025","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/40563592","citation_count":1,"is_preprint":false},{"pmid":"29779329","id":"PMC_29779329","title":"[Mechanisms of recombinant adenovirus-mediated SD-HA fusion protein proliferation inhibition and induced apoptosis of K562 cells].","date":"2018","source":"Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/29779329","citation_count":1,"is_preprint":false},{"pmid":"41635891","id":"PMC_41635891","title":"To screen or not to screen: complexity of SDHA mutation management.","date":"2026","source":"Endocrine oncology (Bristol, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41635891","citation_count":0,"is_preprint":false},{"pmid":"40679525","id":"PMC_40679525","title":"Effect of Ethylmethylhydroxypyridine Succinate on the Expression of PGC-1α, GR, SUCNR1, and SDHA Genes in the Cerebral Cortex of Old Rats during a Course of Dexamethasone Administration.","date":"2025","source":"Bulletin of experimental biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40679525","citation_count":0,"is_preprint":false},{"pmid":"40001192","id":"PMC_40001192","title":"Identification of a novel transcript of mouse Sdha.","date":"2025","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/40001192","citation_count":0,"is_preprint":false},{"pmid":"37577521","id":"PMC_37577521","title":"Flavinated SDHA Underlies the Change in Intrinsic Optical Properties of Oral Cancers.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37577521","citation_count":0,"is_preprint":false},{"pmid":"41613800","id":"PMC_41613800","title":"SDHA Deficiency in Hepatocellular Carcinoma Promotes Tumor Progression through Succinate-Induced M2 Macrophage Polarization.","date":"2026","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/41613800","citation_count":0,"is_preprint":false},{"pmid":"41833598","id":"PMC_41833598","title":"Impact of compound heterozygous SDHA variants on mitochondrial function in pediatric with neurological disease.","date":"2026","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/41833598","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.17.676232","title":"Integrative Analysis of Left Ventricle and Epicardial Adipose Tissue Identifies SDHA and OGDH as Candidate Targets for Ischemic Heart Disease","date":"2025-09-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.17.676232","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.22.677736","title":"Stable reference genes for 24-hour circadian profiling of core clock genes in the blood of obstructive sleep apnea patients","date":"2025-09-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.22.677736","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52620,"output_tokens":5744,"usd":0.12201,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14524,"output_tokens":4734,"usd":0.095485,"stage2_stop_reason":"end_turn"},"total_usd":0.217495,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"X-ray crystal structure of human SDHA in complex with its dedicated assembly factor SDHAF2 was determined. A small-molecule dicarboxylate acts as an essential cofactor that works in synergy with SDHAF2 to orient the flavin and capping domains of SDHA, reorganizing the active site and adjusting the pKa of SDHA R451 to support covalent attachment of the FAD cofactor. Four distinct conformational forms of the complex II flavoprotein were identified and assigned to roles in assembly and catalysis.\",\n      \"method\": \"X-ray crystallography, biochemical reconstitution, structural studies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — X-ray structure combined with biochemical reconstitution and mutagenesis in a single rigorous study; multiple orthogonal methods\",\n      \"pmids\": [\"32887801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In fibroblasts carrying SDHA type I mutations, SDH deficiency leads to succinate accumulation and HIF-1alpha nuclear translocation under normoxic conditions (pseudo-hypoxia). This translocation is independent of superoxide production and cellular iron availability but is inhibited by alpha-ketoglutarate, indicating that the succinate/alpha-KG ratio controls HIF-1alpha prolyl hydroxylase activity in SDH-deficient cells.\",\n      \"method\": \"Cell-based assays in SDHA-mutant fibroblasts, HIF-1alpha nuclear translocation assay, alpha-KG supplementation rescue experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal mechanistic experiments (succinate measurement, HIF-1alpha localization, pharmacological rescue with alpha-KG, ROS independence confirmed), replicated in subsequent studies\",\n      \"pmids\": [\"16195397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A germline SDHA mutation (p.Arg589Trp) causes loss of SDH enzymatic activity in tumor tissue and in a yeast model, and results in pseudo-hypoxia with increased HIF-1alpha and angiogenesis (CD34 upregulation), establishing SDHA as a tumor suppressor gene whose loss-of-function mimics hypoxia via succinate accumulation.\",\n      \"method\": \"Immunohistochemistry, yeast complementation model, in vitro enzymatic activity assay, microarray transcriptome analysis, LOH analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (IHC, yeast functional model, enzymatic assay, transcriptomics) in a single study; replicated by multiple subsequent labs\",\n      \"pmids\": [\"20484225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Proximal inhibition of complex II at SDHA (by RNA interference or pharmacological inhibition) does not increase normoxic ROS production or HIF-alpha stabilization and results in decreased cell growth in vitro and in vivo, in contrast to distal subunit (SdhB) inhibition which increases ROS and HIF-alpha. This distinguishes the mechanism of SDHA loss-of-function from that of SDHB/C/D mutations.\",\n      \"method\": \"RNA interference knockdown, pharmacological complex II inhibition, ROS measurement, HIF-alpha stabilization assay, in vitro and in vivo growth assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal RNAi knockdown of multiple subunits with ROS and HIF readouts, both in vitro and in vivo, in single rigorous study\",\n      \"pmids\": [\"17967865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Nuclear respiratory factor-1 (NRF-1) binds the promoters of SDHa and SDHd (but not SDHB or SDHC) and transcriptionally regulates Complex II expression. NRF-1 silencing specifically decreases SDHa expression, inactivates Complex II, and leads to aerobic HIF-1alpha stabilization and nuclear translocation in cardiomyocytes; this is reversible by high alpha-ketoglutarate concentrations and independent of mitochondrial ROS.\",\n      \"method\": \"Promoter analysis, gene silencing (NRF-1 and SDHa), chromatin immunoprecipitation (ChIP), HIF-1alpha localization assay, succinate oxidation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP confirming NRF-1 binding to SDHa promoter, combined with gene silencing and functional HIF-1alpha readout; multiple orthogonal methods in single study\",\n      \"pmids\": [\"18252725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The assembly factor SDH5/SDHAF2 is protected from LON protease (LONM)-mediated degradation in mitochondria through its stable interaction with SDHA. SDH5(G78R), a paraganglioma-causing mutation, fails to form a stable complex with SDHA and is rapidly degraded by LONM, establishing that SDHA binding is required to stabilize SDHAF2 from proteolytic turnover.\",\n      \"method\": \"Import-chase analysis in isolated human mitochondria, in vitro LON degradation assay, Blue Native PAGE, LONM depletion experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in organello and in vitro reconstitution of SDHA-SDHAF2 interaction and LON-mediated degradation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"24414418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT5 desuccinylates SDHA at lysine K547; this desuccinylation by mimetic mutation (K547R) suppresses SDHA enzymatic activity through inhibition of SDH5/SDHAF2 binding, promoting ccRCC cell proliferation. SIRT5 silencing leads to hypersuccinylation and reactivation of SDHA, confirming SIRT5 as the desuccinylase for SDHA at K547.\",\n      \"method\": \"Tandem mass tag labeling/LC-MS/MS succinylome profiling, site-directed mutagenesis (K547R), Co-IP, SDHA enzymatic activity assay, cell proliferation assay, SIRT5 knockdown\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spec identification of succinylation site plus mutagenesis, Co-IP, and functional enzyme activity assay; single lab\",\n      \"pmids\": [\"30703481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT3-mediated deacetylation of SDHA activates mitochondrial complex II activity and ATP production; in rotenone-induced PD models, SIRT3 activity is suppressed, leading to SDHA hyperacetylation and impaired complex II activity. Activation of SIRT3 (by icariin or honokiol) or overexpression of SDHA rescues complex II activity and protects neurons from rotenone-induced damage.\",\n      \"method\": \"In vivo rat PD model, in vitro MN9D cell model, SIRT3 activation/inhibition, SDHA overexpression, complex II activity assay, ATP measurement, Western blot for acetylated SDHA\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity assay plus post-translational modification readout plus genetic rescue; single lab, two model systems\",\n      \"pmids\": [\"38087172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SDHA/B reduction in HCC leads to succinate accumulation, which facilitates deNEDDylation of cullin1, disrupting the SCF β-TrCP E3 ubiquitin ligase complex, and consequently stabilizing and activating YAP/TAZ. Accelerated cell proliferation and tumor growth caused by SDHA/B depletion or succinate exposure are largely dependent on aberrant YAP/TAZ activation.\",\n      \"method\": \"RNA sequencing, SDHA/B depletion, succinate exposure, Western blot for YAP/TAZ and cullin1 NEDDylation, co-immunoprecipitation, in vitro proliferation and in vivo tumor growth assays\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway established with Co-IP, cullin NEDDylation assay, and rescue experiments; single lab\",\n      \"pmids\": [\"35713976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SDHA gain-of-function germline mutations in patients with persistent polyclonal B cell lymphocytosis (PPBL) lead to accumulation of fumarate in B cells, which engages the KEAP1-Nrf2 system to drive transcription of inflammatory cytokine genes, constituting pathological mitochondrial retrograde signaling.\",\n      \"method\": \"Exome sequencing, extracellular acidification/oxygen consumption rate measurement, metabolite profiling (fumarate), Nrf2 target gene expression analysis, in vivo IL-6 blockade trial\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional metabolomic and transcriptional readouts in patient-derived B cells combined with in vivo therapeutic intervention; single study, multiple methods\",\n      \"pmids\": [\"31527833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MicroRNA-31 (miR-31) suppresses SDHA expression, vital for mitochondrial electron transport chain complex II; miR-31 overexpression lowers SDHA expression and oxygen consumption rates in partially reprogrammed iPSCs, and co-transduction with Yamanaka factors results in a 2.7-fold increase in full reprogramming, establishing a miR-31/SDHA axis that regulates metabolic switching during reprogramming.\",\n      \"method\": \"miR-31 overexpression, SDHA expression measurement, oxygen consumption rate (Seahorse), iPSC reprogramming efficiency assay (TRA1-60 staining)\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct miRNA overexpression with functional metabolic and reprogramming readouts; single lab, multiple methods\",\n      \"pmids\": [\"27346679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Flavin adenine dinucleotide (FAD) covalently bound to SDHA (flavinated SDHA) is responsible for autofluorescence changes in the FAD spectral region in oral squamous cell carcinoma cells; lower levels of flavinated SDHA in OSCC cells result in decreased SDHB levels (since flavinated SDHA is required for functional complexation with SDHB) and altered cellular metabolism.\",\n      \"method\": \"Autofluorescence spectroscopy, SDHA/SDHB protein quantification, metabolic profiling, cell-based assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct measurement of FAD-SDHA autofluorescence and SDHB co-complex dependency; single lab, multiple methods\",\n      \"pmids\": [\"37945749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HINT3 interacts with SDHA and suppresses HDAC1 expression, preventing SDHA deacetylation at K335; this reduces SDH activity and mitochondrial ROS production during cardiac ischemia-reperfusion injury. Cardiomyocyte-specific HINT3 knockout exacerbates myocardial injury and mitochondrial dysfunction, while HINT3 overexpression is protective, establishing the HINT3-HDAC1-SDHA axis in mitochondrial regulation.\",\n      \"method\": \"Mouse cardiac I/R model, cardiomyocyte-specific knockout and overexpression, Co-IP (HINT3-SDHA interaction), HDAC1 expression measurement, SDHA acetylation at K335 assay, SDH activity assay, mitochondrial ROS measurement\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing HINT3-SDHA interaction, site-specific acetylation (K335), SDH activity readout, genetic KO/OE with defined phenotype; single lab\",\n      \"pmids\": [\"40755357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CAV1 (Caveolin-1) directly binds SDHA and triggers its ubiquitination and proteasomal degradation, leading to mitochondrial dysfunction and apoptosis in cardiomyocytes under palmitate conditions; silencing CAV1 reduces apoptosis and improves mitochondrial function in a manner blocked by SDHA knockdown.\",\n      \"method\": \"Co-IP (CAV1-SDHA interaction), ubiquitination assay, CAV1 silencing/overexpression, SDHA knockdown, cell viability and apoptosis assays, mitochondrial function assays, in vivo db/db mouse model\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, epistasis via double knockdown; single lab\",\n      \"pmids\": [\"37804808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EPAS1 (HIF-2α) increases SDHA expression by inhibiting HDAC2 mRNA expression, thereby increasing acetylation at the SDHA histone H3K27 site; this EPAS1-HDAC2-SDHA axis promotes TCA cycle activity and suppresses glycolysis, inhibiting proliferation and invasion of multiple myeloma cells in vitro and in vivo.\",\n      \"method\": \"EPAS1 overexpression/knockdown, HDAC2 modulation, ChIP for H3K27 acetylation at SDHA locus, SDHA expression assay, metabolic flux (TCA vs glycolysis), in vitro and in vivo proliferation assays\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement by overexpression/KD with metabolic and proliferation readouts; single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"41290982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SDHA mutations lead to concurrent loss of both SDHA and SDHB protein expression (demonstrated by Western blotting and immunohistochemistry in GIST patients), indicating that SDHA protein is required for stability of SDHB within the complex II holocomplex.\",\n      \"method\": \"Western blotting, immunohistochemistry, next-generation sequencing, LOH analysis\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — consistently replicated across multiple independent cohort studies (PMIDs 21505157, 22974104, 23612575) demonstrating SDHA loss leads to SDHB loss\",\n      \"pmids\": [\"21505157\", \"22974104\", \"23612575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Using an SDHA-knockout cell line with Bxb1-mediated variant reintroduction, cancer-associated SDHA missense variants can be distinguished from non-cancer variants by the degree of SDH enzymatic dysfunction they cause; SDH activity data predict cancer pathogenicity with performance exceeding computational tools, providing a functional assay for clinical variant classification.\",\n      \"method\": \"SDHA-knockout cell line, Bxb1-mediated recombination for variant introduction, SDH activity assay, logistic regression for pathogenicity prediction\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct enzymatic activity measurement in defined cell model for 72 variants; single lab, rigorous design\",\n      \"pmids\": [\"39321216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SDHA splicing mutations (c.64-2A>G and c.1065-3C>A) result in loss of SDHA protein expression; the missense mutation c.565T>G severely affects SDHA enzymatic activity. Pathogenicity of c.565T>G was confirmed by lentiviral complementation experiments in patient fibroblasts.\",\n      \"method\": \"mRNA splicing analysis, protein expression (Western blot), enzymatic activity assay, lentiviral complementation in patient fibroblasts\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lentiviral complementation confirming loss of function, enzymatic activity assay; single lab, multiple methods\",\n      \"pmids\": [\"24781757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Recessive SDHA mutations cause isolated complex II deficiency; Western blotting and BN-PAGE studies confirmed decreased steady-state levels of SDH subunits and impaired complex II assembly in patient-derived samples with compound heterozygous SDHA mutations.\",\n      \"method\": \"Western blot, BN-PAGE (Blue Native PAGE), biochemical complex II activity measurement, yeast complementation\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BN-PAGE assembly analysis plus enzymatic activity in patient-derived fibroblasts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22972948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Compound heterozygous SDHA variants (p.R512Q and p.R585W) cause significant decreases in SDH activity, SDH subunit levels, and impaired complex II assembly in patient-derived fibroblasts; additionally, complex I activity and CI-containing supercomplex formation were impaired, though basal and maximal respiration rates remained unchanged while spare respiratory capacity was significantly reduced.\",\n      \"method\": \"Patient-derived fibroblast analysis, SDH enzymatic activity assay, BN-PAGE for assembly, complex I activity assay, Seahorse respirometry\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple enzymatic and assembly assays in patient-derived cells; single lab\",\n      \"pmids\": [\"41833598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Yeast Saccharomyces cerevisiae complementation assays demonstrated that biallelic SDHA mutations found in a pediatric patient with seizures and behavioral dysregulation are functionally deleterious to mitochondrial complex II function.\",\n      \"method\": \"Yeast complementation assay, mitochondrial respiratory chain activity measurement, muscle biopsy biochemistry\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — yeast complementation as functional validation; single case study, single lab\",\n      \"pmids\": [\"40045913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A heterozygous de novo SDHA variant (p.Arg662Cys) causes considerably decreased complex II residual activity in patient-derived fibroblasts and lymphocytes. Protein modeling suggests this substitution compromises FAD-binding to SDHA at the C-terminus, impairing FAD binding and decreasing entire complex II activity.\",\n      \"method\": \"Complex II enzymatic activity assay in patient fibroblasts and lymphocytes, protein structural modeling\",\n      \"journal\": \"Metabolic brain disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — enzymatic activity in patient cells plus computational structural prediction; single case, single lab\",\n      \"pmids\": [\"33471299\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SDHA encodes the catalytic flavoprotein subunit of mitochondrial complex II (succinate dehydrogenase), where it covalently binds FAD (flavination facilitated by assembly factor SDHAF2 and a dicarboxylate cofactor that repositions the active site and adjusts pKa of R451) to oxidize succinate to fumarate; loss of SDHA enzymatic activity causes succinate accumulation that inhibits HIF prolyl hydroxylases, driving pseudo-hypoxic HIF-1alpha stabilization and tumor suppressor phenotypes, while SDHA activity is post-translationally regulated by SIRT3-mediated deacetylation (activating) and SIRT5-mediated desuccinylation at K547 (inhibitory), CAV1-mediated ubiquitin-proteasomal degradation, and HINT3/HDAC1-controlled acetylation at K335; SDHA protein also stabilizes its assembly factor SDHAF2 from LON protease degradation, and its loss destabilizes SDHB within the mature complex.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SDHA encodes the catalytic flavoprotein subunit of mitochondrial complex II (succinate dehydrogenase), whose enzymatic activity oxidizes succinate to fumarate and links the TCA cycle to the electron transport chain [#1, #18]. Maturation of SDHA requires covalent flavination: structural and biochemical reconstitution show that the dedicated assembly factor SDHAF2, acting in synergy with a small-molecule dicarboxylate cofactor, reorients the flavin and capping domains and adjusts the pKa of R451 to support covalent FAD attachment [#0], and flavinated SDHA is in turn required for productive complexation with and stabilization of SDHB [#11, #15]. SDHA loss-of-function abolishes complex II assembly and activity, causing succinate accumulation that inhibits HIF prolyl hydroxylases and drives normoxic (pseudo-hypoxic) HIF-1alpha stabilization in a manner controlled by the succinate/alpha-ketoglutarate ratio and independent of ROS and iron availability [#1, #2]; this establishes SDHA as a tumor suppressor whose biallelic or splicing/missense mutations cause isolated complex II deficiency and disease [#2, #17, #18]. Notably, proximal inhibition at SDHA differs mechanistically from distal SDHB/C/D loss, failing to elevate ROS and instead reducing cell growth [#3], and accumulated metabolites can act through additional effectors including YAP/TAZ stabilization via cullin1 deNEDDylation [#8] and fumarate-driven KEAP1-Nrf2 inflammatory signaling [#9]. SDHA expression and activity are tightly regulated: NRF-1 transcriptionally controls SDHA promoter activity [#4], and the protein is post-translationally tuned by SIRT5-mediated desuccinylation at K547 (inhibitory, via disruption of SDHAF2 binding) [#6], SIRT3-mediated deacetylation (activating) [#7], HINT3/HDAC1-controlled acetylation at K335 [#12], and CAV1-mediated ubiquitin-proteasomal degradation [#13]. Reciprocally, SDHA binding protects its assembly factor SDHAF2 from LON protease degradation [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the central mechanism by which SDHA loss causes disease: that SDH deficiency raises succinate and stabilizes HIF-1alpha under normoxia, distinguishing this from ROS- or iron-dependent routes.\",\n      \"evidence\": \"Cell-based assays in SDHA-mutant fibroblasts with HIF-1alpha localization and alpha-KG rescue\",\n      \"pmids\": [\"16195397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which prolyl hydroxylase isoform is rate-limiting\", \"Did not establish in vivo tumorigenic consequences\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Distinguished the mechanism of SDHA (proximal) loss from SDHB/C/D (distal) loss, showing SDHA knockdown does not elevate ROS or HIF-alpha and instead reduces growth.\",\n      \"evidence\": \"Reciprocal RNAi of complex II subunits with ROS, HIF, and growth readouts in vitro and in vivo\",\n      \"pmids\": [\"17967865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apparent contradiction with later HIF-1alpha stabilization findings in SDHA-mutant cells not fully reconciled\", \"Molecular basis of differential ROS production between subunits unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified transcriptional control of SDHA, showing NRF-1 binds the SDHa promoter and regulates complex II expression with downstream HIF-1alpha consequences.\",\n      \"evidence\": \"Promoter analysis, ChIP, NRF-1/SDHa silencing, and HIF-1alpha localization in cardiomyocytes\",\n      \"pmids\": [\"18252725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-regulators at the SDHa promoter not defined\", \"Tissue specificity of NRF-1 control not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Formally established SDHA as a tumor suppressor by tying a germline mutation to loss of enzymatic activity, pseudo-hypoxia, and angiogenesis.\",\n      \"evidence\": \"IHC, yeast complementation, enzyme assay, transcriptomics and LOH on a p.Arg589Trp tumor\",\n      \"pmids\": [\"20484225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single mutation studied\", \"Tissue-specific penetrance of SDHA tumorigenesis not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed that SDHA protein is required for SDHB stability and complex II assembly, providing a structural rationale for combined subunit loss in patients.\",\n      \"evidence\": \"Western blot, IHC, BN-PAGE, and yeast complementation in GIST and complex II-deficient patient samples\",\n      \"pmids\": [\"21505157\", \"22974104\", \"23612575\", \"22972948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the stoichiometric/structural basis of SDHB destabilization\", \"Whether residual SDHA fragments retain partial function unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a reciprocal stabilization mechanism: SDHA binding protects assembly factor SDHAF2 from LON protease degradation, and a paraganglioma mutation breaks this interaction.\",\n      \"evidence\": \"Import-chase in isolated mitochondria, in vitro LON degradation assay, BN-PAGE, and LONM depletion\",\n      \"pmids\": [\"24414418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of this stabilization to flavination kinetics not measured\", \"Other proteases not excluded\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined post-translational regulation of SDHA activity, showing SIRT5 desuccinylates K547 to suppress activity by impairing SDHAF2 binding.\",\n      \"evidence\": \"Succinylome MS, K547R mutagenesis, Co-IP, enzyme activity assays, and SIRT5 knockdown in ccRCC cells\",\n      \"pmids\": [\"30703481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Stoichiometry of endogenous K547 succinylation in normal tissue not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded SDHA pathology beyond loss-of-function by linking gain-of-function variants to fumarate accumulation and KEAP1-Nrf2 inflammatory signaling.\",\n      \"evidence\": \"Exome sequencing, respirometry, fumarate metabolite profiling, Nrf2 target analysis, and in vivo IL-6 blockade in PPBL patients\",\n      \"pmids\": [\"31527833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of how variants produce gain-of-function unclear\", \"Single patient cohort\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Solved how SDHA acquires its FAD cofactor: a structure showing SDHAF2 plus a dicarboxylate cofactor reorient the flavin/capping domains and tune R451 pKa for covalent flavination.\",\n      \"evidence\": \"X-ray crystallography of the SDHA-SDHAF2 complex with biochemical reconstitution and mutagenesis\",\n      \"pmids\": [\"32887801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of flavination relative to SDHB incorporation in vivo not fully resolved\", \"Identity/source of the physiological dicarboxylate not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a HIF-independent oncogenic route, in which SDHA/B loss-derived succinate deNEDDylates cullin1 to stabilize YAP/TAZ.\",\n      \"evidence\": \"RNA-seq, depletion/succinate exposure, NEDDylation and Co-IP assays, and tumor growth assays in HCC\",\n      \"pmids\": [\"35713976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct succinate target on the deNEDDylation machinery not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed SIRT3 deacetylation activates complex II and is protective, linking SDHA acetylation status to neuronal injury.\",\n      \"evidence\": \"Rotenone PD rat/MN9D models with SIRT3 modulation, SDHA overexpression, activity and acetylation readouts\",\n      \"pmids\": [\"38087172\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific acetylated lysines not mapped\", \"Direct vs indirect SIRT3-SDHA action not distinguished\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated CAV1 directly binds SDHA and drives its ubiquitin-proteasomal degradation, coupling lipotoxic stress to mitochondrial dysfunction.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assay, CAV1/SDHA epistasis knockdowns, and db/db mouse model\",\n      \"pmids\": [\"37804808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating CAV1-dependent SDHA ubiquitination not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected SDHA flavination state to SDHB levels and cellular metabolism, showing low flavinated SDHA reduces SDHB in cancer cells.\",\n      \"evidence\": \"Autofluorescence spectroscopy, SDHA/SDHB quantification, and metabolic profiling in OSCC cells\",\n      \"pmids\": [\"37945749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cause of reduced flavination in OSCC not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Translated mechanistic knowledge into a functional pathogenicity classifier, scoring SDHA missense variants by enzymatic dysfunction.\",\n      \"evidence\": \"SDHA-knockout cell line with Bxb1 variant reintroduction and SDH activity-based logistic regression on 72 variants\",\n      \"pmids\": [\"39321216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not capture non-enzymatic (e.g. gain-of-function or assembly) variant effects\", \"Single lab assay\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added an acetylation-control axis, with HINT3 suppressing HDAC1 to maintain SDHA K335 acetylation and restrain SDH activity and ROS in cardiac ischemia-reperfusion.\",\n      \"evidence\": \"Cardiac I/R mouse model with cardiomyocyte HINT3 KO/OE, Co-IP, K335 acetylation, and SDH activity assays\",\n      \"pmids\": [\"40755357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect HINT3-HDAC1-SDHA wiring not fully dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple, sometimes opposing regulatory inputs on SDHA (acetylation, succinylation, ubiquitination, transcription) are integrated in a given tissue and reconciled with the divergent ROS/HIF outcomes of proximal versus distal complex II loss remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model integrating PTM crosstalk on SDHA\", \"Tissue-specific dominance of each regulator undetermined\", \"Quantitative relationship between flavination, assembly, and downstream succinate signaling not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 2, 3, 16, 18]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0050660\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5, 7, 12, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2, 8, 9, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 9, 15, 16, 18]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 2, 9]}\n    ],\n    \"complexes\": [\n      \"mitochondrial complex II (succinate dehydrogenase)\"\n    ],\n    \"partners\": [\n      \"SDHAF2\",\n      \"SDHB\",\n      \"SIRT5\",\n      \"SIRT3\",\n      \"HINT3\",\n      \"CAV1\",\n      \"LONP1\",\n      \"NRF1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}