{"gene":"SUCLA2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2021,"finding":"SUCLA2 physically associates with kidney-type glutaminase (GLS) and suppresses GLS K311 succinylation. Upon oxidative stress, p38 MAPK phosphorylates SUCLA2 at S79, causing SUCLA2 to dissociate from GLS. Dissociation allows enhanced GLS K311 succinylation, GLS oligomerization, and increased GLS activity, boosting glutaminolysis and NADPH/glutathione production to counteract oxidative stress.","method":"Co-immunoprecipitation, in vitro kinase assay (p38 MAPK phosphorylation of SUCLA2 S79), site-directed mutagenesis of SUCLA2 S79 and GLS K311, mass spectrometry for succinylation, mouse tumor xenograft models","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, kinase assay, mutagenesis, MS, in vivo) in a single rigorous study establishing mechanism","pmids":["33991485"],"is_preprint":false},{"year":2025,"finding":"Upon IGF1 stimulation, ERK2 phosphorylates SUCLA2 at S124, and PIN1-mediated cis-trans isomerization of SUCLA2 facilitates its interaction with OXCT1 (a rate-limiting ketolysis enzyme). SUCLA2-associated with OXCT1 generates succinyl-CoA that directly succinylates OXCT1 at K421, activating OXCT1 and enhancing ketolysis in HCC cells.","method":"Co-immunoprecipitation, in vitro kinase assay (ERK2 phosphorylation of SUCLA2 S124), site-directed mutagenesis (SUCLA2 S124, OXCT1 K421), mass spectrometry for succinylation, mouse tumor models, PIN1 inhibitor experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal biochemical methods (Co-IP, kinase assay, mutagenesis, MS) combined with in vivo validation in a single study","pmids":["39862868"],"is_preprint":false},{"year":2020,"finding":"Loss-of-function mutations in SUCLA2 cause accumulation of succinyl-CoA, leading to global protein hyper-succinylation across cellular compartments. Nearly 1,000 succinylation sites on 366 proteins were quantified in patient-derived cells. Many hyper-succinylated targets are known substrates of the desuccinylase SIRT5; SIRT5 gain-of-function in a zebrafish sucla2-deficient model reduced global succinylation and improved survival.","method":"Mass spectrometry quantification of succinylation sites in patient-derived fibroblasts and myotubes, zebrafish sucla2 KO model with SIRT5 gain-of-function rescue, metabolite measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — quantitative MS proteomics plus in vivo genetic rescue with SIRT5 in zebrafish model, multiple orthogonal methods","pmids":["33230181"],"is_preprint":false},{"year":2011,"finding":"In SUCLA2-deficient patient fibroblasts, mtDNA content and NDPK activity are normal; however, shRNA knockdown of the GDP-dependent isoform SUCLG2 in both patient and control fibroblasts caused significant mtDNA depletion, decreased NDPK and cytochrome c oxidase activities, and marked growth impairment, indicating that SUCLG2 (not SUCLA2) is the primary driver of mtDNA maintenance, and that mitochondrial NDPK links succinyl-CoA synthetase activity to mtDNA maintenance.","method":"shRNA knockdown of SUCLG2 in patient and control fibroblasts, mtDNA quantification, NDPK activity assay, cytochrome c oxidase activity assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with multiple biochemical readouts in a single lab; negative result for SUCLA2 itself is mechanistically informative","pmids":["21295139"],"is_preprint":false},{"year":2012,"finding":"ALAS2 (erythroid aminolevulinic acid synthase) binds to SUCLA2 via its carboxyl-terminal region. XLSA mutations in the ALAS2 C-terminus (p.Met567Val, p.Ser568Gly, p.Phe557Ter) abolish binding to a SUCLA2 affinity column despite normal ALAS2 enzymatic activity, indicating that the ALAS2–SUCLA2 interaction is required for normal in vivo ALAS2 activity in heme biosynthesis.","method":"SUCLA2 affinity column pulldown with recombinant ALAS2 wild-type and mutant proteins, enzymatic activity and kinetics assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity pulldown with multiple mutants and enzymatic validation in a single study","pmids":["22740690"],"is_preprint":false},{"year":2024,"finding":"SIRT5 desuccinylates SUCLA2 at K118; SIRT5 downregulation leads to SUCLA2 K118 hyper-succinylation, which inhibits succinyl-CoA synthetase activity, causing succinyl-CoA accumulation and a feed-forward cycle of further SUCLA2 succinylation. This dysregulation propagates TCA cycle dysfunction and contributes to mitochondrial damage via hypersuccinylation of CYC1 (complex III subunit) and activation of the cGAS-STING pathway in acute pancreatitis.","method":"Colorimetric enzyme activity assays, mass spectrometry, site-directed mutagenesis (SUCLA2 K118), adenovirus-mediated SIRT5 overexpression, SUCLA2 knockdown, in vitro and in vivo AP models","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-directed mutagenesis and MS with functional enzyme assay and in vivo model, single lab","pmids":["39643219"],"is_preprint":false},{"year":2025,"finding":"In adipose tissue macrophages, ATP generated from glutaminolysis suppresses AMPK, which decreases phosphorylation of SUCLA2. Reduced SUCLA2 phosphorylation activates succinyl-CoA synthetase, causing overproduction of succinate and IL-1β. siRNA-mediated SUCLA2 knockdown in mice reduced HFD-induced obesity, demonstrating that the glutaminolysis/AMPK/SUCLA2/IL-1β axis controls macrophage-driven inflammatory obesity.","method":"siRNA knockdown of SUCLA2 in mice, AMPKα myeloid cell knockout, IL-1β neutralization, metabolite measurements, phosphorylation analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic and pharmacological perturbations with metabolite and inflammatory readouts, single lab","pmids":["39966410"],"is_preprint":false},{"year":2013,"finding":"In human cerebral cortex, SUCLA2 protein (A-SUCL-β) is expressed exclusively in neurons and colocalizes >99% with the mitochondrial F0-F1 ATP synthase d subunit; it is absent in GFAP- and S100-positive astroglia. SUCLA2 mRNA was also detected only in neurons, not glial cells, by in situ hybridization.","method":"Immunofluorescence with cell-type markers on surgical human cortical tissue, in situ hybridization, Western blot, negative control using SUCLA2-null patient fibroblasts","journal":"Brain structure & function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence with multiple markers and validated antibody specificity; single lab","pmids":["24085565"],"is_preprint":false},{"year":2014,"finding":"In human cerebral cortex, SUCLG2 (GTP-forming β subunit) is absent in neurons, astrocytes, microglia, and oligodendrocytes but localizes to cerebrovascular structures, confirming that succinyl-CoA ligase substrate-level phosphorylation is restricted to neurons (SUCLA2) and vascular cells (SUCLG2) in the human brain.","method":"Double immunofluorescence with Iba1, myelin basic protein, mitotracker, GFAP, S100, and SUCLA2/SUCLG2 antibodies on surgical human cortical tissue and fibroblast cultures","journal":"Journal of bioenergetics and biomembranes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct co-localization with multiple validated cell-type markers; single lab extending prior study","pmids":["25370487"],"is_preprint":false},{"year":2024,"finding":"Muscle-specific conditional knockout of Sucla2 (using HSA-Cre with CRISPR-generated floxed allele) in mice produces mitochondrial myopathy with reduced body weight, grip strength, and exercise tolerance. The soleus (slow-twitch, oxidative) muscle was more severely affected than the EDL (fast-twitch), showing 40% reduced specific tetanic force, slower contraction/relaxation, ~3-fold increase in mitochondria, and nearly doubled proportion of Type 1 myosin heavy chain fibers.","method":"Conditional Cre-Lox Sucla2 knockout in skeletal muscle, RT-qPCR, Western blot, LC-MS/MS enzyme activity assay, ex vivo muscle contractility, immunohistochemistry for fiber types, COX/SDH staining","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with multiple orthogonal functional and morphological readouts; single lab","pmids":["39482887"],"is_preprint":false},{"year":2026,"finding":"In sucla2-/- zebrafish, excess succinyl-CoA drives bulk protein succinylation that consumes NAD+, impairing mitochondrial respiratory function and causing locomotor deficits. NAD+ precursor supplementation (nicotinamide, nicotinamide riboside) restores NAD+ levels and improves locomotion and survival; this effect requires the NAD+-dependent desuccinylase Sirt5, which enhances oxidative metabolism and urea cycle nitrogen elimination.","method":"Zebrafish sucla2 knockout model, NAD+ metabolite measurements, behavioral locomotor assays, Sirt5 genetic requirement testing, metabolomics","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo zebrafish model with genetic and pharmacological interventions and multiple biochemical readouts; single lab","pmids":["41574612"],"is_preprint":false},{"year":2016,"finding":"Knockdown of Sucla2 in mouse spermatocyte GC2 cells decreased mitochondrial membrane potential, reduced ATP production, increased ROS, decreased Bcl2 expression, and induced apoptosis, demonstrating that SUCLA2 mitochondrial function is required for spermatocyte viability.","method":"siRNA knockdown in GC2 mouse spermatocyte cells, flow cytometry (MMP, apoptosis, ROS), luminometric ATP assay, Western blot (Bcl2), immunohistochemistry for localization in testis","journal":"Folia histochemica et cytobiologica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single cell line, partial mechanistic follow-up without pathway placement","pmids":["27766610"],"is_preprint":false},{"year":2025,"finding":"SUCLA2 overexpression reduced succinyl-CoA levels and inhibited lysine succinylation of SHMT2, suppressing ferroptosis and renal interstitial fibrosis in Ang II-treated cells and mice. SIRT5-mediated desuccinylation of SHMT2 also inhibited ferroptosis, and the anti-ferroptotic effect of SUCLA2 overexpression was abolished by SHMT2 silencing, placing SUCLA2 upstream of SHMT2 succinylation in the ferroptosis pathway.","method":"Adeno-associated virus-mediated SUCLA2 overexpression in mice, SHMT2 siRNA knockdown, succinylome analysis, metabolite measurements, ferroptosis markers","journal":"FASEB journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, multiple methods but indirect evidence for SUCLA2-SHMT2 succinylation link without direct in vitro reconstitution","pmids":["41359112"],"is_preprint":false}],"current_model":"SUCLA2 encodes the ADP-forming β subunit of mitochondrial succinyl-CoA synthetase/ligase (SCS), which catalyzes reversible conversion of succinyl-CoA to succinate coupled to ATP synthesis in the TCA cycle; beyond this core metabolic role, SUCLA2 directly binds and regulates substrate proteins (GLS, OXCT1, ALAS2) by controlling local succinyl-CoA availability for their post-translational succinylation, and its own activity is regulated by phosphorylation (p38 MAPK at S79; ERK2 at S124; AMPK-dependent sites) and by SIRT5-mediated desuccinylation at K118, with loss-of-function causing global protein hyper-succinylation, NAD+ depletion, mtDNA depletion (particularly when SUCLG2 is also compromised), and tissue-specific encephalomyopathy most severely affecting neurons where SUCLA2 is exclusively expressed."},"narrative":{"mechanistic_narrative":"SUCLA2 encodes the ADP-forming β subunit of mitochondrial succinyl-CoA synthetase, the TCA-cycle enzyme whose control over local succinyl-CoA availability makes it a central regulator of protein lysine succinylation across cellular compartments [PMID:33230181]. Loss of SUCLA2 function causes succinyl-CoA accumulation and global protein hyper-succinylation (nearly 1,000 sites on hundreds of proteins), many of which are SIRT5 substrates; SIRT5 gain-of-function reverses this and improves survival in sucla2-deficient zebrafish [PMID:33230181]. This succinylation-buffering role lets SUCLA2 act as a direct regulator of partner enzymes: it physically associates with glutaminase (GLS) to suppress GLS K311 succinylation, and p38 MAPK phosphorylation at S79 dissociates the complex to license GLS succinylation, oligomerization and glutaminolysis under oxidative stress [PMID:33991485]; ERK2 phosphorylation at S124, coupled to PIN1 isomerization, redirects SUCLA2 to OXCT1, where locally generated succinyl-CoA succinylates and activates OXCT1 to drive ketolysis [PMID:39862868]. SUCLA2 also binds ALAS2 through the ALAS2 C-terminus, an interaction required for normal heme-biosynthetic ALAS2 activity in vivo [PMID:22740690]. SUCLA2 activity is itself gated by post-translational control: SIRT5 desuccinylates SUCLA2 at K118 and AMPK-dependent phosphorylation tunes its output, with loss of these controls inhibiting the enzyme and propagating TCA-cycle and mitochondrial dysfunction [PMID:39643219, PMID:39966410]. The protein's catalytic loss produces tissue-specific disease, reflecting its expression pattern: in human cerebral cortex SUCLA2 is restricted to neurons and absent from glia, with SUCLG2 instead serving vascular cells [PMID:24085565, PMID:25370487]. Muscle-specific knockout produces a mitochondrial myopathy preferentially affecting oxidative slow-twitch fibers [PMID:39482887], and NAD+ depletion driven by bulk succinylation underlies respiratory and locomotor deficits that NAD+ precursor supplementation rescues in a SIRT5-dependent manner [PMID:41574612].","teleology":[{"year":2011,"claim":"Tested whether SUCLA2 itself maintains mtDNA, resolving which succinyl-CoA synthetase isoform links the enzyme to mitochondrial genome integrity.","evidence":"shRNA knockdown of SUCLG2 versus assessment of SUCLA2-deficient patient fibroblasts, with mtDNA, NDPK and cytochrome c oxidase readouts","pmids":["21295139"],"confidence":"Medium","gaps":["Does not explain how SUCLA2 loss causes neuronal disease without overt mtDNA depletion","Mechanism by which NDPK couples SCS to mtDNA maintenance not resolved at molecular level"]},{"year":2012,"claim":"Identified ALAS2 as a physical partner of SUCLA2, establishing a non-canonical role linking SCS to heme biosynthesis.","evidence":"SUCLA2 affinity-column pulldown of recombinant wild-type and XLSA-mutant ALAS2 with enzymatic kinetics","pmids":["22740690"],"confidence":"Medium","gaps":["No structural model of the ALAS2–SUCLA2 interface","Whether succinyl-CoA channeling rather than binding per se drives the effect not tested"]},{"year":2013,"claim":"Defined the cell-type expression of SUCLA2 in human brain, explaining the neuronal selectivity of SUCLA2-related encephalomyopathy.","evidence":"Immunofluorescence with cell-type markers, in situ hybridization and Western blot on human cortical tissue with SUCLA2-null fibroblast controls","pmids":["24085565"],"confidence":"Medium","gaps":["Does not establish why neurons cannot compensate via SUCLG2","Single-region cortical sampling"]},{"year":2014,"claim":"Mapped SUCLG2 distribution to cerebrovascular cells, confirming a mutually exclusive division of substrate-level phosphorylation between neurons and vasculature.","evidence":"Double immunofluorescence with multiple glial, microglial and vascular markers on human cortex","pmids":["25370487"],"confidence":"Medium","gaps":["Functional consequence of vascular-restricted SUCLG2 not tested","No quantitative comparison of flux contributions"]},{"year":2020,"claim":"Established that SUCLA2 loss drives global protein hyper-succinylation, reframing the enzyme as a regulator of the cellular succinylome rather than a purely metabolic component.","evidence":"Quantitative succinylome mass spectrometry in patient cells plus SIRT5 gain-of-function rescue in a sucla2-knockout zebrafish model","pmids":["33230181"],"confidence":"High","gaps":["Which hyper-succinylated targets are pathogenically decisive not pinpointed","Compartment-specific succinyl-CoA dynamics not directly measured"]},{"year":2021,"claim":"Showed SUCLA2 directly regulates a partner enzyme's succinylation, with p38 MAPK phosphorylation acting as a stress-responsive switch controlling glutaminolysis.","evidence":"Co-IP, in vitro p38 kinase assay, S79/K311 mutagenesis, succinylation MS and xenograft models","pmids":["33991485"],"confidence":"High","gaps":["Whether dissociation increases bulk or only GLS-local succinyl-CoA not distinguished","Generality of the dissociation switch beyond oxidative stress unclear"]},{"year":2024,"claim":"Demonstrated SUCLA2 activity is governed by SIRT5-mediated desuccinylation at K118, defining a feed-forward loop linking SUCLA2 inactivation to mitochondrial damage.","evidence":"K118 mutagenesis, MS, colorimetric enzyme assays, SIRT5 overexpression and SUCLA2 knockdown in acute pancreatitis models","pmids":["39643219"],"confidence":"Medium","gaps":["Stoichiometry and kinetics of K118 succinylation on activity not quantified","Direct link from CYC1 succinylation to cGAS-STING activation indirect"]},{"year":2024,"claim":"A clean muscle-specific knockout established SUCLA2 as required for oxidative muscle function, with fiber-type selectivity matching metabolic demand.","evidence":"Conditional Cre-Lox Sucla2 knockout in skeletal muscle with contractility, fiber-type and mitochondrial morphology readouts","pmids":["39482887"],"confidence":"Medium","gaps":["Molecular basis of soleus-versus-EDL vulnerability not defined","Succinylation status of muscle proteins not profiled"]},{"year":2025,"claim":"Extended the partner-regulation paradigm to OXCT1, showing ERK2/PIN1-dependent recruitment of SUCLA2 activates ketolysis through targeted succinylation.","evidence":"Co-IP, ERK2 kinase assay, S124/K421 mutagenesis, succinylation MS, PIN1 inhibition and mouse tumor models in HCC","pmids":["39862868"],"confidence":"High","gaps":["How a TCA enzyme delivers succinyl-CoA selectively to a bound partner not structurally resolved","Whether the OXCT1 and GLS modes operate simultaneously not addressed"]},{"year":2025,"claim":"Placed SUCLA2 in an AMPK-controlled inflammatory axis in macrophages, where dephosphorylation activates SCS to overproduce succinate and IL-1β.","evidence":"siRNA SUCLA2 knockdown, myeloid AMPKα knockout, IL-1β neutralization and metabolite measurements in diet-induced obesity mice","pmids":["39966410"],"confidence":"Medium","gaps":["AMPK phosphorylation sites on SUCLA2 not mapped","Direct demonstration that succinate alone drives IL-1β incomplete"]},{"year":2026,"claim":"Identified NAD+ depletion by bulk succinylation as the cause of respiratory and behavioral deficits in SUCLA2 deficiency, and showed NAD+ precursor rescue requires Sirt5.","evidence":"Zebrafish sucla2 knockout with NAD+ metabolite profiling, behavioral assays, NAD+ precursor supplementation and Sirt5 genetic-requirement testing","pmids":["41574612"],"confidence":"Medium","gaps":["Translation of NAD+ precursor benefit to mammalian/patient settings untested","Quantitative contribution of succinylation to NAD+ consumption not isolated"]},{"year":null,"claim":"How SUCLA2 achieves selective, partner-directed succinyl-CoA delivery versus indiscriminate global succinylation, and how its multiple phosphorylation and desuccinylation marks are integrated, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of SUCLA2 bound to GLS, OXCT1 or ALAS2","No reconstitution distinguishing local channeling from bulk succinyl-CoA flux","Cross-talk among S79, S124, K118 and AMPK-dependent modifications not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[2,5]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[7,11]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,5,6]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2]}],"complexes":["succinyl-CoA synthetase (SCS)"],"partners":["GLS","OXCT1","ALAS2","SIRT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P2R7","full_name":"Succinate--CoA ligase [ADP-forming] subunit beta, mitochondrial","aliases":["ATP-specific succinyl-CoA synthetase subunit beta","A-SCS","Itaconyl--CoA ligase [ADP-forming] subunit beta","Malyl--CoA ligase [ADP-forming] subunit beta","Succinyl-CoA synthetase beta-A chain","SCS-betaA"],"length_aa":463,"mass_kda":50.3,"function":"ATP-specific succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of ATP and thus represents the only step of substrate-level phosphorylation in the TCA (PubMed:15877282, PubMed:34492704, PubMed:40108300). The beta subunit provides nucleotide specificity of the enzyme and binds the substrate succinate, while the binding sites for coenzyme A and phosphate are found in the alpha subunit (By similarity). Also able to act as an ATP-specific itaconyl- and malyl-CoA synthetase (PubMed:40108300)","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9P2R7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SUCLA2","classification":"Not Classified","n_dependent_lines":127,"n_total_lines":1208,"dependency_fraction":0.10513245033112582},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SUCLA2","total_profiled":1310},"omim":[{"mim_id":"612073","title":"MITOCHONDRIAL DNA DEPLETION SYNDROME 5 (ENCEPHALOMYOPATHIC WITH OR WITHOUT METHYLMALONIC ACIDURIA); MTDPS5","url":"https://www.omim.org/entry/612073"},{"mim_id":"611224","title":"SUCCINATE-CoA LIGASE, GDP/ADP-FORMING, SUBUNIT ALPHA; SUCLG1","url":"https://www.omim.org/entry/611224"},{"mim_id":"610141","title":"QT INTERVAL, VARIATION IN","url":"https://www.omim.org/entry/610141"},{"mim_id":"603922","title":"SUCCINATE-CoA LIGASE, GDP-FORMING, SUBUNIT BETA; SUCLG2","url":"https://www.omim.org/entry/603922"},{"mim_id":"603921","title":"SUCCINATE-CoA LIGASE, ADP-FORMING, SUBUNIT BETA; SUCLA2","url":"https://www.omim.org/entry/603921"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":217.4},{"tissue":"tongue","ntpm":253.9}],"url":"https://www.proteinatlas.org/search/SUCLA2"},"hgnc":{"alias_symbol":[],"prev_symbol":["LINC00444"]},"alphafold":{"accession":"Q9P2R7","domains":[{"cath_id":"3.30.1490.20","chopping":"73-158","consensus_level":"high","plddt":94.7324,"start":73,"end":158},{"cath_id":"3.30.470.20","chopping":"162-289","consensus_level":"high","plddt":96.4841,"start":162,"end":289},{"cath_id":"3.40.50.261","chopping":"298-452","consensus_level":"high","plddt":92.6786,"start":298,"end":452}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2R7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2R7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2R7-F1-predicted_aligned_error_v6.png","plddt_mean":87.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SUCLA2","jax_strain_url":"https://www.jax.org/strain/search?query=SUCLA2"},"sequence":{"accession":"Q9P2R7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P2R7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P2R7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2R7"}},"corpus_meta":[{"pmid":"33991485","id":"PMC_33991485","title":"SUCLA2-coupled regulation of GLS succinylation and activity counteracts oxidative stress in tumor cells.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/33991485","citation_count":166,"is_preprint":false},{"pmid":"17301081","id":"PMC_17301081","title":"SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness.","date":"2007","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/17301081","citation_count":155,"is_preprint":false},{"pmid":"17287286","id":"PMC_17287286","title":"Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations.","date":"2007","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/17287286","citation_count":146,"is_preprint":false},{"pmid":"33230181","id":"PMC_33230181","title":"SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33230181","citation_count":71,"is_preprint":false},{"pmid":"26475597","id":"PMC_26475597","title":"Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients.","date":"2015","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/26475597","citation_count":71,"is_preprint":false},{"pmid":"21295139","id":"PMC_21295139","title":"The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion.","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21295139","citation_count":48,"is_preprint":false},{"pmid":"22740690","id":"PMC_22740690","title":"X-linked sideroblastic anemia due to carboxyl-terminal ALAS2 mutations that cause loss of binding to the β-subunit of succinyl-CoA synthetase (SUCLA2).","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22740690","citation_count":42,"is_preprint":false},{"pmid":"19666145","id":"PMC_19666145","title":"Dystonia and deafness due to SUCLA2 defect; Clinical course and biochemical markers in 16 children.","date":"2009","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/19666145","citation_count":41,"is_preprint":false},{"pmid":"23010432","id":"PMC_23010432","title":"A novel homozygous mutation in SUCLA2 gene identified by exome sequencing.","date":"2012","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23010432","citation_count":36,"is_preprint":false},{"pmid":"39862868","id":"PMC_39862868","title":"OXCT1 succinylation and activation by SUCLA2 promotes ketolysis and liver tumor growth.","date":"2025","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/39862868","citation_count":22,"is_preprint":false},{"pmid":"27913098","id":"PMC_27913098","title":"Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion.","date":"2016","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/27913098","citation_count":22,"is_preprint":false},{"pmid":"24986829","id":"PMC_24986829","title":"Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion.","date":"2014","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/24986829","citation_count":21,"is_preprint":false},{"pmid":"39966410","id":"PMC_39966410","title":"Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39966410","citation_count":20,"is_preprint":false},{"pmid":"24085565","id":"PMC_24085565","title":"Exclusive neuronal expression of SUCLA2 in the human 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neurology","url":"https://pubmed.ncbi.nlm.nih.gov/27651038","citation_count":14,"is_preprint":false},{"pmid":"32694611","id":"PMC_32694611","title":"Pharmacologically targetable vulnerability in prostate cancer carrying RB1-SUCLA2 deletion.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32694611","citation_count":13,"is_preprint":false},{"pmid":"26863601","id":"PMC_26863601","title":"Influences of XDH genotype by gene-gene interactions with SUCLA2 for thiopurine-induced leukopenia in Korean patients with Crohn's disease.","date":"2016","source":"Scandinavian journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/26863601","citation_count":9,"is_preprint":false},{"pmid":"25582465","id":"PMC_25582465","title":"[SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome: a case report and review of literature].","date":"2014","source":"Zhonghua er ke za zhi = Chinese journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/25582465","citation_count":8,"is_preprint":false},{"pmid":"26409464","id":"PMC_26409464","title":"SUCLA2 Deficiency: A Deafness-Dystonia Syndrome with Distinctive Metabolic Findings (Report of a New Patient and Review of the Literature).","date":"2015","source":"JIMD reports","url":"https://pubmed.ncbi.nlm.nih.gov/26409464","citation_count":8,"is_preprint":false},{"pmid":"33231368","id":"PMC_33231368","title":"SUCLA2 Arg407Trp mutation can cause a nonprogressive movement disorder - deafness syndrome.","date":"2020","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33231368","citation_count":6,"is_preprint":false},{"pmid":"39482887","id":"PMC_39482887","title":"Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes.","date":"2024","source":"Journal of cachexia, sarcopenia and muscle","url":"https://pubmed.ncbi.nlm.nih.gov/39482887","citation_count":4,"is_preprint":false},{"pmid":"39643219","id":"PMC_39643219","title":"SIRT5 mediated succinylation of SUCLA2 regulates TCA cycle dysfunction and mitochondrial damage in pancreatic acinar cells in acute pancreatitis.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39643219","citation_count":3,"is_preprint":false},{"pmid":"26952923","id":"PMC_26952923","title":"Novel mutation in SUCLA2 identified on sequencing analysis.","date":"2016","source":"Pediatrics international : official journal of the Japan Pediatric Society","url":"https://pubmed.ncbi.nlm.nih.gov/26952923","citation_count":3,"is_preprint":false},{"pmid":"27766610","id":"PMC_27766610","title":"Knockdown of Sucla2 decreases the viability of mouse spermatocytes by inducing apoptosis through injury of the mitochondrial function of cells.","date":"2016","source":"Folia histochemica et cytobiologica","url":"https://pubmed.ncbi.nlm.nih.gov/27766610","citation_count":3,"is_preprint":false},{"pmid":"41359112","id":"PMC_41359112","title":"SUCLA2 Inhibited Lysine Succinylation of SHMT2 to Suppress Ferroptosis and Renal Interstitial Fibrosis.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41359112","citation_count":2,"is_preprint":false},{"pmid":"41574612","id":"PMC_41574612","title":"NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.","date":"2026","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/41574612","citation_count":0,"is_preprint":false},{"pmid":"39070054","id":"PMC_39070054","title":"Two novel SUCLA2 variants cause mitochondrial DNA depletion syndrome, type 5 in two siblings.","date":"2024","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/39070054","citation_count":0,"is_preprint":false},{"pmid":"28749033","id":"PMC_28749033","title":"Co-occurring Down syndrome and SUCLA2-related mitochondrial depletion syndrome.","date":"2017","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/28749033","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.20.25333965","title":"Complementarity of long-read sequencing and optical genome mapping in Parkinson’s disease","date":"2025-08-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.20.25333965","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18365,"output_tokens":3942,"usd":0.057112,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11786,"output_tokens":3993,"usd":0.079378,"stage2_stop_reason":"end_turn"},"total_usd":0.13649,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"SUCLA2 physically associates with kidney-type glutaminase (GLS) and suppresses GLS K311 succinylation. Upon oxidative stress, p38 MAPK phosphorylates SUCLA2 at S79, causing SUCLA2 to dissociate from GLS. Dissociation allows enhanced GLS K311 succinylation, GLS oligomerization, and increased GLS activity, boosting glutaminolysis and NADPH/glutathione production to counteract oxidative stress.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay (p38 MAPK phosphorylation of SUCLA2 S79), site-directed mutagenesis of SUCLA2 S79 and GLS K311, mass spectrometry for succinylation, mouse tumor xenograft models\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, kinase assay, mutagenesis, MS, in vivo) in a single rigorous study establishing mechanism\",\n      \"pmids\": [\"33991485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Upon IGF1 stimulation, ERK2 phosphorylates SUCLA2 at S124, and PIN1-mediated cis-trans isomerization of SUCLA2 facilitates its interaction with OXCT1 (a rate-limiting ketolysis enzyme). SUCLA2-associated with OXCT1 generates succinyl-CoA that directly succinylates OXCT1 at K421, activating OXCT1 and enhancing ketolysis in HCC cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay (ERK2 phosphorylation of SUCLA2 S124), site-directed mutagenesis (SUCLA2 S124, OXCT1 K421), mass spectrometry for succinylation, mouse tumor models, PIN1 inhibitor experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal biochemical methods (Co-IP, kinase assay, mutagenesis, MS) combined with in vivo validation in a single study\",\n      \"pmids\": [\"39862868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss-of-function mutations in SUCLA2 cause accumulation of succinyl-CoA, leading to global protein hyper-succinylation across cellular compartments. Nearly 1,000 succinylation sites on 366 proteins were quantified in patient-derived cells. Many hyper-succinylated targets are known substrates of the desuccinylase SIRT5; SIRT5 gain-of-function in a zebrafish sucla2-deficient model reduced global succinylation and improved survival.\",\n      \"method\": \"Mass spectrometry quantification of succinylation sites in patient-derived fibroblasts and myotubes, zebrafish sucla2 KO model with SIRT5 gain-of-function rescue, metabolite measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — quantitative MS proteomics plus in vivo genetic rescue with SIRT5 in zebrafish model, multiple orthogonal methods\",\n      \"pmids\": [\"33230181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In SUCLA2-deficient patient fibroblasts, mtDNA content and NDPK activity are normal; however, shRNA knockdown of the GDP-dependent isoform SUCLG2 in both patient and control fibroblasts caused significant mtDNA depletion, decreased NDPK and cytochrome c oxidase activities, and marked growth impairment, indicating that SUCLG2 (not SUCLA2) is the primary driver of mtDNA maintenance, and that mitochondrial NDPK links succinyl-CoA synthetase activity to mtDNA maintenance.\",\n      \"method\": \"shRNA knockdown of SUCLG2 in patient and control fibroblasts, mtDNA quantification, NDPK activity assay, cytochrome c oxidase activity assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with multiple biochemical readouts in a single lab; negative result for SUCLA2 itself is mechanistically informative\",\n      \"pmids\": [\"21295139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ALAS2 (erythroid aminolevulinic acid synthase) binds to SUCLA2 via its carboxyl-terminal region. XLSA mutations in the ALAS2 C-terminus (p.Met567Val, p.Ser568Gly, p.Phe557Ter) abolish binding to a SUCLA2 affinity column despite normal ALAS2 enzymatic activity, indicating that the ALAS2–SUCLA2 interaction is required for normal in vivo ALAS2 activity in heme biosynthesis.\",\n      \"method\": \"SUCLA2 affinity column pulldown with recombinant ALAS2 wild-type and mutant proteins, enzymatic activity and kinetics assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity pulldown with multiple mutants and enzymatic validation in a single study\",\n      \"pmids\": [\"22740690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT5 desuccinylates SUCLA2 at K118; SIRT5 downregulation leads to SUCLA2 K118 hyper-succinylation, which inhibits succinyl-CoA synthetase activity, causing succinyl-CoA accumulation and a feed-forward cycle of further SUCLA2 succinylation. This dysregulation propagates TCA cycle dysfunction and contributes to mitochondrial damage via hypersuccinylation of CYC1 (complex III subunit) and activation of the cGAS-STING pathway in acute pancreatitis.\",\n      \"method\": \"Colorimetric enzyme activity assays, mass spectrometry, site-directed mutagenesis (SUCLA2 K118), adenovirus-mediated SIRT5 overexpression, SUCLA2 knockdown, in vitro and in vivo AP models\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed mutagenesis and MS with functional enzyme assay and in vivo model, single lab\",\n      \"pmids\": [\"39643219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In adipose tissue macrophages, ATP generated from glutaminolysis suppresses AMPK, which decreases phosphorylation of SUCLA2. Reduced SUCLA2 phosphorylation activates succinyl-CoA synthetase, causing overproduction of succinate and IL-1β. siRNA-mediated SUCLA2 knockdown in mice reduced HFD-induced obesity, demonstrating that the glutaminolysis/AMPK/SUCLA2/IL-1β axis controls macrophage-driven inflammatory obesity.\",\n      \"method\": \"siRNA knockdown of SUCLA2 in mice, AMPKα myeloid cell knockout, IL-1β neutralization, metabolite measurements, phosphorylation analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic and pharmacological perturbations with metabolite and inflammatory readouts, single lab\",\n      \"pmids\": [\"39966410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In human cerebral cortex, SUCLA2 protein (A-SUCL-β) is expressed exclusively in neurons and colocalizes >99% with the mitochondrial F0-F1 ATP synthase d subunit; it is absent in GFAP- and S100-positive astroglia. SUCLA2 mRNA was also detected only in neurons, not glial cells, by in situ hybridization.\",\n      \"method\": \"Immunofluorescence with cell-type markers on surgical human cortical tissue, in situ hybridization, Western blot, negative control using SUCLA2-null patient fibroblasts\",\n      \"journal\": \"Brain structure & function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence with multiple markers and validated antibody specificity; single lab\",\n      \"pmids\": [\"24085565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In human cerebral cortex, SUCLG2 (GTP-forming β subunit) is absent in neurons, astrocytes, microglia, and oligodendrocytes but localizes to cerebrovascular structures, confirming that succinyl-CoA ligase substrate-level phosphorylation is restricted to neurons (SUCLA2) and vascular cells (SUCLG2) in the human brain.\",\n      \"method\": \"Double immunofluorescence with Iba1, myelin basic protein, mitotracker, GFAP, S100, and SUCLA2/SUCLG2 antibodies on surgical human cortical tissue and fibroblast cultures\",\n      \"journal\": \"Journal of bioenergetics and biomembranes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct co-localization with multiple validated cell-type markers; single lab extending prior study\",\n      \"pmids\": [\"25370487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Muscle-specific conditional knockout of Sucla2 (using HSA-Cre with CRISPR-generated floxed allele) in mice produces mitochondrial myopathy with reduced body weight, grip strength, and exercise tolerance. The soleus (slow-twitch, oxidative) muscle was more severely affected than the EDL (fast-twitch), showing 40% reduced specific tetanic force, slower contraction/relaxation, ~3-fold increase in mitochondria, and nearly doubled proportion of Type 1 myosin heavy chain fibers.\",\n      \"method\": \"Conditional Cre-Lox Sucla2 knockout in skeletal muscle, RT-qPCR, Western blot, LC-MS/MS enzyme activity assay, ex vivo muscle contractility, immunohistochemistry for fiber types, COX/SDH staining\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with multiple orthogonal functional and morphological readouts; single lab\",\n      \"pmids\": [\"39482887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In sucla2-/- zebrafish, excess succinyl-CoA drives bulk protein succinylation that consumes NAD+, impairing mitochondrial respiratory function and causing locomotor deficits. NAD+ precursor supplementation (nicotinamide, nicotinamide riboside) restores NAD+ levels and improves locomotion and survival; this effect requires the NAD+-dependent desuccinylase Sirt5, which enhances oxidative metabolism and urea cycle nitrogen elimination.\",\n      \"method\": \"Zebrafish sucla2 knockout model, NAD+ metabolite measurements, behavioral locomotor assays, Sirt5 genetic requirement testing, metabolomics\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo zebrafish model with genetic and pharmacological interventions and multiple biochemical readouts; single lab\",\n      \"pmids\": [\"41574612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Knockdown of Sucla2 in mouse spermatocyte GC2 cells decreased mitochondrial membrane potential, reduced ATP production, increased ROS, decreased Bcl2 expression, and induced apoptosis, demonstrating that SUCLA2 mitochondrial function is required for spermatocyte viability.\",\n      \"method\": \"siRNA knockdown in GC2 mouse spermatocyte cells, flow cytometry (MMP, apoptosis, ROS), luminometric ATP assay, Western blot (Bcl2), immunohistochemistry for localization in testis\",\n      \"journal\": \"Folia histochemica et cytobiologica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell line, partial mechanistic follow-up without pathway placement\",\n      \"pmids\": [\"27766610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SUCLA2 overexpression reduced succinyl-CoA levels and inhibited lysine succinylation of SHMT2, suppressing ferroptosis and renal interstitial fibrosis in Ang II-treated cells and mice. SIRT5-mediated desuccinylation of SHMT2 also inhibited ferroptosis, and the anti-ferroptotic effect of SUCLA2 overexpression was abolished by SHMT2 silencing, placing SUCLA2 upstream of SHMT2 succinylation in the ferroptosis pathway.\",\n      \"method\": \"Adeno-associated virus-mediated SUCLA2 overexpression in mice, SHMT2 siRNA knockdown, succinylome analysis, metabolite measurements, ferroptosis markers\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, multiple methods but indirect evidence for SUCLA2-SHMT2 succinylation link without direct in vitro reconstitution\",\n      \"pmids\": [\"41359112\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SUCLA2 encodes the ADP-forming β subunit of mitochondrial succinyl-CoA synthetase/ligase (SCS), which catalyzes reversible conversion of succinyl-CoA to succinate coupled to ATP synthesis in the TCA cycle; beyond this core metabolic role, SUCLA2 directly binds and regulates substrate proteins (GLS, OXCT1, ALAS2) by controlling local succinyl-CoA availability for their post-translational succinylation, and its own activity is regulated by phosphorylation (p38 MAPK at S79; ERK2 at S124; AMPK-dependent sites) and by SIRT5-mediated desuccinylation at K118, with loss-of-function causing global protein hyper-succinylation, NAD+ depletion, mtDNA depletion (particularly when SUCLG2 is also compromised), and tissue-specific encephalomyopathy most severely affecting neurons where SUCLA2 is exclusively expressed.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SUCLA2 encodes the ADP-forming β subunit of mitochondrial succinyl-CoA synthetase, the TCA-cycle enzyme whose control over local succinyl-CoA availability makes it a central regulator of protein lysine succinylation across cellular compartments [#2]. Loss of SUCLA2 function causes succinyl-CoA accumulation and global protein hyper-succinylation (nearly 1,000 sites on hundreds of proteins), many of which are SIRT5 substrates; SIRT5 gain-of-function reverses this and improves survival in sucla2-deficient zebrafish [#2]. This succinylation-buffering role lets SUCLA2 act as a direct regulator of partner enzymes: it physically associates with glutaminase (GLS) to suppress GLS K311 succinylation, and p38 MAPK phosphorylation at S79 dissociates the complex to license GLS succinylation, oligomerization and glutaminolysis under oxidative stress [#0]; ERK2 phosphorylation at S124, coupled to PIN1 isomerization, redirects SUCLA2 to OXCT1, where locally generated succinyl-CoA succinylates and activates OXCT1 to drive ketolysis [#1]. SUCLA2 also binds ALAS2 through the ALAS2 C-terminus, an interaction required for normal heme-biosynthetic ALAS2 activity in vivo [#4]. SUCLA2 activity is itself gated by post-translational control: SIRT5 desuccinylates SUCLA2 at K118 and AMPK-dependent phosphorylation tunes its output, with loss of these controls inhibiting the enzyme and propagating TCA-cycle and mitochondrial dysfunction [#5, #6]. The protein's catalytic loss produces tissue-specific disease, reflecting its expression pattern: in human cerebral cortex SUCLA2 is restricted to neurons and absent from glia, with SUCLG2 instead serving vascular cells [#7, #8]. Muscle-specific knockout produces a mitochondrial myopathy preferentially affecting oxidative slow-twitch fibers [#9], and NAD+ depletion driven by bulk succinylation underlies respiratory and locomotor deficits that NAD+ precursor supplementation rescues in a SIRT5-dependent manner [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Tested whether SUCLA2 itself maintains mtDNA, resolving which succinyl-CoA synthetase isoform links the enzyme to mitochondrial genome integrity.\",\n      \"evidence\": \"shRNA knockdown of SUCLG2 versus assessment of SUCLA2-deficient patient fibroblasts, with mtDNA, NDPK and cytochrome c oxidase readouts\",\n      \"pmids\": [\"21295139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not explain how SUCLA2 loss causes neuronal disease without overt mtDNA depletion\", \"Mechanism by which NDPK couples SCS to mtDNA maintenance not resolved at molecular level\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified ALAS2 as a physical partner of SUCLA2, establishing a non-canonical role linking SCS to heme biosynthesis.\",\n      \"evidence\": \"SUCLA2 affinity-column pulldown of recombinant wild-type and XLSA-mutant ALAS2 with enzymatic kinetics\",\n      \"pmids\": [\"22740690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the ALAS2–SUCLA2 interface\", \"Whether succinyl-CoA channeling rather than binding per se drives the effect not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the cell-type expression of SUCLA2 in human brain, explaining the neuronal selectivity of SUCLA2-related encephalomyopathy.\",\n      \"evidence\": \"Immunofluorescence with cell-type markers, in situ hybridization and Western blot on human cortical tissue with SUCLA2-null fibroblast controls\",\n      \"pmids\": [\"24085565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish why neurons cannot compensate via SUCLG2\", \"Single-region cortical sampling\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped SUCLG2 distribution to cerebrovascular cells, confirming a mutually exclusive division of substrate-level phosphorylation between neurons and vasculature.\",\n      \"evidence\": \"Double immunofluorescence with multiple glial, microglial and vascular markers on human cortex\",\n      \"pmids\": [\"25370487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of vascular-restricted SUCLG2 not tested\", \"No quantitative comparison of flux contributions\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that SUCLA2 loss drives global protein hyper-succinylation, reframing the enzyme as a regulator of the cellular succinylome rather than a purely metabolic component.\",\n      \"evidence\": \"Quantitative succinylome mass spectrometry in patient cells plus SIRT5 gain-of-function rescue in a sucla2-knockout zebrafish model\",\n      \"pmids\": [\"33230181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which hyper-succinylated targets are pathogenically decisive not pinpointed\", \"Compartment-specific succinyl-CoA dynamics not directly measured\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed SUCLA2 directly regulates a partner enzyme's succinylation, with p38 MAPK phosphorylation acting as a stress-responsive switch controlling glutaminolysis.\",\n      \"evidence\": \"Co-IP, in vitro p38 kinase assay, S79/K311 mutagenesis, succinylation MS and xenograft models\",\n      \"pmids\": [\"33991485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether dissociation increases bulk or only GLS-local succinyl-CoA not distinguished\", \"Generality of the dissociation switch beyond oxidative stress unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated SUCLA2 activity is governed by SIRT5-mediated desuccinylation at K118, defining a feed-forward loop linking SUCLA2 inactivation to mitochondrial damage.\",\n      \"evidence\": \"K118 mutagenesis, MS, colorimetric enzyme assays, SIRT5 overexpression and SUCLA2 knockdown in acute pancreatitis models\",\n      \"pmids\": [\"39643219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and kinetics of K118 succinylation on activity not quantified\", \"Direct link from CYC1 succinylation to cGAS-STING activation indirect\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A clean muscle-specific knockout established SUCLA2 as required for oxidative muscle function, with fiber-type selectivity matching metabolic demand.\",\n      \"evidence\": \"Conditional Cre-Lox Sucla2 knockout in skeletal muscle with contractility, fiber-type and mitochondrial morphology readouts\",\n      \"pmids\": [\"39482887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of soleus-versus-EDL vulnerability not defined\", \"Succinylation status of muscle proteins not profiled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the partner-regulation paradigm to OXCT1, showing ERK2/PIN1-dependent recruitment of SUCLA2 activates ketolysis through targeted succinylation.\",\n      \"evidence\": \"Co-IP, ERK2 kinase assay, S124/K421 mutagenesis, succinylation MS, PIN1 inhibition and mouse tumor models in HCC\",\n      \"pmids\": [\"39862868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a TCA enzyme delivers succinyl-CoA selectively to a bound partner not structurally resolved\", \"Whether the OXCT1 and GLS modes operate simultaneously not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed SUCLA2 in an AMPK-controlled inflammatory axis in macrophages, where dephosphorylation activates SCS to overproduce succinate and IL-1β.\",\n      \"evidence\": \"siRNA SUCLA2 knockdown, myeloid AMPKα knockout, IL-1β neutralization and metabolite measurements in diet-induced obesity mice\",\n      \"pmids\": [\"39966410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AMPK phosphorylation sites on SUCLA2 not mapped\", \"Direct demonstration that succinate alone drives IL-1β incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified NAD+ depletion by bulk succinylation as the cause of respiratory and behavioral deficits in SUCLA2 deficiency, and showed NAD+ precursor rescue requires Sirt5.\",\n      \"evidence\": \"Zebrafish sucla2 knockout with NAD+ metabolite profiling, behavioral assays, NAD+ precursor supplementation and Sirt5 genetic-requirement testing\",\n      \"pmids\": [\"41574612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Translation of NAD+ precursor benefit to mammalian/patient settings untested\", \"Quantitative contribution of succinylation to NAD+ consumption not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SUCLA2 achieves selective, partner-directed succinyl-CoA delivery versus indiscriminate global succinylation, and how its multiple phosphorylation and desuccinylation marks are integrated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of SUCLA2 bound to GLS, OXCT1 or ALAS2\", \"No reconstitution distinguishing local channeling from bulk succinyl-CoA flux\", \"Cross-talk among S79, S124, K118 and AMPK-dependent modifications not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 5, 6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\"succinyl-CoA synthetase (SCS)\"],\n    \"partners\": [\"GLS\", \"OXCT1\", \"ALAS2\", \"SIRT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}