{"gene":"SUCLA2","run_date":"2026-04-28T21:42:57","timeline":{"discoveries":[{"year":2021,"finding":"SUCLA2 acts as a regulator of GLS (kidney-type glutaminase) succinylation: under oxidative stress, p38 MAPK phosphorylates SUCLA2 at S79, causing SUCLA2 to dissociate from GLS, which leads to enhanced GLS K311 succinylation, GLS oligomerization, and increased GLS activity, thereby boosting glutaminolysis and NADPH/glutathione production to counteract oxidative stress.","method":"Co-immunoprecipitation, site-directed mutagenesis (S79A/D, K311R), in vitro succinylation assay, mouse tumor xenograft models, mass spectrometry","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including mutagenesis, biochemical assays, and in vivo validation in single highly-cited study","pmids":["33991485"],"is_preprint":false},{"year":2025,"finding":"Upon IGF1 stimulation, ERK2 phosphorylates SUCLA2 at S124, followed by PIN1-mediated cis-trans isomerization of SUCLA2, enabling SUCLA2 to interact with OXCT1 (3-oxoacid CoA-transferase 1). SUCLA2-associated with OXCT1 generates succinyl-CoA, which directly succinylates OXCT1 at K421, activating OXCT1 and promoting ketolysis and HCC tumor growth.","method":"Co-immunoprecipitation, site-directed mutagenesis (S124A/D, K421R), in vitro succinylation assay, mouse tumor models, mass spectrometry","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including mutagenesis, biochemical reconstitution, and in vivo tumor models","pmids":["39862868"],"is_preprint":false},{"year":2020,"finding":"Loss-of-function mutations in SUCLA2 cause succinyl-CoA accumulation and global protein hyper-succinylation across cellular compartments in patient-derived fibroblasts and myotubes; SIRT5 gain-of-function reduces global protein succinylation and improves survival in a zebrafish model of SCL deficiency, establishing succinyl-CoA-driven protein succinylation as a pathomechanism.","method":"Mass spectrometry quantification of ~1,000 succinylation sites, SIRT5 gain-of-function in zebrafish model, patient-derived fibroblasts and myotubes","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — proteome-wide MS quantification combined with genetic rescue in zebrafish model, moderate evidence from a single lab with multiple orthogonal methods","pmids":["33230181"],"is_preprint":false},{"year":2012,"finding":"SUCLA2 (β-subunit of succinyl-CoA synthetase) physically binds to ALAS2 (erythroid aminolevulinic acid synthase) via ALAS2's carboxyl-terminal region; XLSA mutations in ALAS2 exon 11 (p.Met567Val, p.Ser568Gly) and a truncation (p.Phe557Ter) abolish binding to SUCLA2 without affecting intrinsic ALAS2 enzymatic activity, implicating the ALAS2-SUCLA2 complex in regulation of erythroid heme biosynthesis.","method":"SUCLA2 affinity column pulldown with recombinant mutant ALAS2 proteins, enzymatic kinetics assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — affinity pulldown with multiple mutant proteins and kinetic characterization, single lab","pmids":["22740690"],"is_preprint":false},{"year":2011,"finding":"SUCLG2 (GDP-forming β-subunit isoform) compensates for SUCLA2 deficiency in fibroblasts; knockdown of SUCLG2 by shRNA in SUCLA2-deficient patient fibroblasts causes significant decreases in mtDNA content, NDPK activity, and cytochrome c oxidase activity, establishing that mitochondrial NDPK association is linked to mtDNA maintenance and that SUCLG2 is more critical than SUCLA2 for mtDNA maintenance in fibroblasts.","method":"shRNA knockdown of SUCLG2 in patient-derived fibroblasts, quantification of mtDNA, NDPK activity assay, cytochrome c oxidase activity assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockdown with multiple enzymatic readouts in patient-derived cells, single lab","pmids":["21295139"],"is_preprint":false},{"year":2013,"finding":"SUCLA2 protein (A-SUCL-β) is expressed exclusively in neurons in the human cerebral cortex, co-localizing >99% with mitochondrial F0-F1 ATP synthase d-subunit; it is absent in GFAP- and S100-positive astrocytes and confirmed absent by both immunofluorescence and in situ hybridization. Glial cells lack both SUCLA2 and SUCLG2, consistent with alternative metabolic pathways (GABA shunt, ketone body metabolism) in glia.","method":"Immunofluorescence with cell-type markers, in situ hybridization, Western blotting, patient fibroblast negative control (complete SUCLA2 deletion)","journal":"Brain structure & function","confidence":"Medium","confidence_rationale":"Tier 2 — direct immunohistochemistry and ISH with orthogonal markers and patient-derived negative control, single lab","pmids":["24085565"],"is_preprint":false},{"year":2007,"finding":"Mutations in SUCLA2 (encoding the ADP-forming β-subunit of succinyl-CoA ligase) cause accumulation of succinyl-CoA, which inhibits conversion of methylmalonyl-CoA to succinyl-CoA and leads to elevated methylmalonic acid; this is accompanied by mtDNA depletion, establishing SUCLA2 as essential for TCA cycle function and mtDNA maintenance.","method":"Genetic analysis, homozygosity mapping, metabolite profiling (urine MMA, plasma lactate, carnitine esters), protein-level confirmation in patient samples","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and biochemical characterization in multiple patient cohorts, replicated across two independent cohorts (PMID 17287286 and 17301081)","pmids":["17287286","17301081"],"is_preprint":false},{"year":2024,"finding":"SIRT5 downregulation leads to SUCLA2 hypersuccinylation at K118, which inhibits succinyl-CoA synthetase activity, causing a vicious cycle of succinyl-CoA accumulation and further SUCLA2 succinylation; SIRT5 overexpression or SUCLA2 knockdown attenuates TCA cycle dysregulation, protein hypersuccinylation, and mitochondrial damage in acute pancreatitis models.","method":"Colorimetric succinyl-CoA synthetase activity assay, mass spectrometry, site-directed mutagenesis (K118R), adenovirus-mediated SIRT5 overexpression, in vitro and in vivo AP models","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 1–2 — mutagenesis, MS, enzymatic activity assay, and genetic rescue, single lab with moderate evidence","pmids":["39643219"],"is_preprint":false},{"year":2025,"finding":"In adipose tissue macrophages, ATP generated from glutaminolysis suppresses AMPK, which decreases phosphorylation of SUCLA2 β-subunit, thereby activating succinyl-CoA synthetase and leading to overproduction of succinate and IL-1β; SUCLA2 knockdown by siRNA reduces obesity in HFD-fed mice, placing SUCLA2 in a glutaminolysis/AMPK/SUCLA2/IL-1β inflammatory axis.","method":"siRNA knockdown of SUCLA2 in mice, AMPK genetic knockout in myeloid cells, IL-1β neutralization, phosphorylation analysis, metabolic phenotyping","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pharmacologic interventions with mechanistic pathway placement, single lab","pmids":["39966410"],"is_preprint":false},{"year":2025,"finding":"SUCLA2 negatively regulates lysine succinylation of SHMT2; overexpression of SUCLA2 reduces succinyl-CoA levels and SHMT2 succinylation, thereby inhibiting ferroptosis in Ang II-induced renal fibrosis models; SIRT5-mediated desuccinylation of SHMT2 mimics this effect, and the anti-ferroptotic effect of SUCLA2 overexpression is reversed by SHMT2 silencing.","method":"SUCLA2 overexpression via AAV in mouse kidneys, SHMT2 siRNA knockdown, succinylation profiling, ferroptosis assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — genetic gain/loss-of-function with epistasis rescue experiment, single lab","pmids":["41359112"],"is_preprint":false},{"year":2016,"finding":"Knockdown of Sucla2 in mouse GC2 spermatocytes decreases cell viability, mitochondrial membrane potential, ATP production, and Bcl2 expression, and increases ROS and apoptosis, establishing a direct role for SUCLA2 in maintaining mitochondrial function and cell survival in spermatocytes.","method":"siRNA knockdown in GC2 cells, flow cytometry (MMP, apoptosis, ROS), ATP luminometric assay, Western blot","journal":"Folia histochemica et cytobiologica","confidence":"Low","confidence_rationale":"Tier 3 — single method per endpoint, single lab, no pathway placement beyond mitochondrial dysfunction","pmids":["27766610"],"is_preprint":false},{"year":2026,"finding":"In sucla2-/- zebrafish, excess succinyl-CoA drives bulk protein succinylation that consumes NAD+, propagating mitochondrial respiratory defects and locomotor impairment; NAD+ precursor supplementation restores NAD+ levels and requires the desuccinylase Sirt5 to improve oxidative metabolism and survival, mechanistically linking succinylation-driven NAD+ depletion to mitochondrial bioenergetics failure.","method":"sucla2-/- zebrafish model, behavioral locomotor assays, NAD+ metabolite quantification, Sirt5 genetic manipulation, NAD+ precursor supplementation (nicotinamide, nicotinamide riboside)","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — genetic model with pharmacological and genetic rescue, multiple readouts, single lab","pmids":["41574612"],"is_preprint":false},{"year":2024,"finding":"Muscle-specific conditional knockout of Sucla2 in mice (using HSA-Cre) yields mitochondrial myopathy with reduced body weight, grip strength, and exercise capacity; soleus muscles show 40% less specific tetanic force and a ~2-fold increase in Type 1 myosin heavy chain fibers and mitochondrial content, while EDL muscles are comparatively unaffected, establishing muscle-type-specific consequences of SUCLA2 loss.","method":"Cre-lox conditional knockout, ex vivo contractility measurements, fiber-type immunostaining, COX/SDH histochemistry, RT-qPCR, Western blot, serum metabolite mass spectrometry","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2 — clean conditional KO with multiple orthogonal phenotypic readouts, single lab","pmids":["39482887"],"is_preprint":false}],"current_model":"SUCLA2 encodes the ADP-forming β-subunit of the mitochondrial succinyl-CoA synthetase (ligase), which catalyzes reversible conversion of succinyl-CoA to succinate with coupled ADP phosphorylation in the TCA cycle; beyond its canonical enzymatic role, SUCLA2 acts as a direct regulator of protein succinylation by controlling local succinyl-CoA availability — it physically associates with substrate enzymes (GLS, OXCT1, SHMT2) and its p38/ERK2-mediated phosphorylation (at S79 or S124) governs these interactions, modulating succinylation-dependent activation or inhibition of target enzymes in cancer metabolism, ketolysis, and stress responses; loss of SUCLA2 causes succinyl-CoA accumulation, global protein hyper-succinylation, NAD+ depletion, and mtDNA depletion, explaining the encephalomyopathy and mitochondrial disease phenotypes observed in patients."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing SUCLA2 as an essential TCA cycle enzyme whose loss causes mtDNA depletion and methylmalonic aciduria resolved the genetic basis of a mitochondrial encephalomyopathy.","evidence":"Homozygosity mapping, mutation identification, and metabolite profiling in multiple patient cohorts","pmids":["17287286","17301081"],"confidence":"Medium","gaps":["Mechanism linking succinyl-CoA ligase deficiency to mtDNA depletion was not established","No direct enzymatic activity measurement in patient tissues","Tissue-specific consequences of SUCLA2 loss not explored"]},{"year":2011,"claim":"Demonstrating that SUCLG2 compensates for SUCLA2 loss in fibroblasts and that mitochondrial NDPK association is linked to mtDNA maintenance clarified why mtDNA depletion occurs in SUCLA2-deficient tissues.","evidence":"shRNA knockdown of SUCLG2 in SUCLA2-deficient patient fibroblasts with mtDNA, NDPK, and cytochrome c oxidase quantification","pmids":["21295139"],"confidence":"Medium","gaps":["NDPK-mtDNA maintenance mechanism not molecularly dissected","Compensation dynamics not tested in neuronal or muscle tissue where disease manifests"]},{"year":2012,"claim":"The discovery that SUCLA2 physically binds ALAS2 and that XLSA mutations disrupt this interaction without affecting ALAS2 catalysis revealed SUCLA2 as a scaffold for substrate channeling in heme biosynthesis.","evidence":"Affinity pulldown of recombinant wild-type and mutant ALAS2 proteins on SUCLA2 columns with kinetic assays","pmids":["22740690"],"confidence":"Medium","gaps":["Functional consequence of SUCLA2-ALAS2 disruption on heme synthesis rates not measured in cells","No reciprocal Co-IP or in vivo validation","Structural basis of the interaction unknown"]},{"year":2013,"claim":"Showing that SUCLA2 is expressed exclusively in neurons (not glia) in human cortex explained why SUCLA2 deficiency preferentially causes encephalopathy and why glial cells rely on alternative metabolic pathways.","evidence":"Immunofluorescence co-localization with neuronal and glial markers, in situ hybridization, and SUCLA2-null patient fibroblast negative control in human cortex","pmids":["24085565"],"confidence":"Medium","gaps":["Glial metabolic compensation not functionally tested","Expression pattern not confirmed across brain regions beyond cortex"]},{"year":2020,"claim":"Proteome-wide succinylation profiling of SUCLA2-deficient cells and rescue by SIRT5 gain-of-function in zebrafish established protein hypersuccinylation as a direct pathomechanism rather than simply a biomarker of disease.","evidence":"Quantitative MS of ~1,000 succinylation sites in patient fibroblasts/myotubes; SIRT5 gain-of-function rescue in zebrafish SCL deficiency model","pmids":["33230181"],"confidence":"High","gaps":["Specific succinylation targets driving pathology not identified","Whether succinylation or succinyl-CoA accumulation per se is more pathogenic remained unclear"]},{"year":2021,"claim":"Demonstrating that p38-mediated phosphorylation of SUCLA2 at S79 controls its dissociation from GLS and thereby regulates GLS succinylation and glutaminolysis transformed the view of SUCLA2 from a passive metabolic enzyme to an active, signal-responsive regulator of protein succinylation.","evidence":"Co-IP, S79A/D and K311R mutagenesis, in vitro succinylation assay, and mouse tumor xenograft models","pmids":["33991485"],"confidence":"High","gaps":["Whether SUCLA2 scaffold function is general across all succinylation substrates or target-specific","Structural basis of phosphorylation-induced dissociation not determined"]},{"year":2024,"claim":"Conditional muscle-specific Sucla2 knockout revealed that slow-twitch (soleus) fibers are selectively vulnerable to SUCLA2 loss, establishing muscle-type-specific bioenergetic consequences and fiber-type remodeling as features of the myopathy.","evidence":"Cre-lox conditional knockout (HSA-Cre), ex vivo contractility, fiber-type immunostaining, and serum metabolomics in mice","pmids":["39482887"],"confidence":"Medium","gaps":["Molecular basis of differential vulnerability between soleus and EDL not defined","Contribution of protein succinylation vs. bioenergetic deficit to myopathy not dissected"]},{"year":2024,"claim":"Identification of SUCLA2 K118 as a feedback succinylation site inhibiting its own enzymatic activity, regulated by SIRT5, established a vicious-cycle mechanism in which SUCLA2 inactivation amplifies succinyl-CoA accumulation in acute pancreatitis.","evidence":"K118R mutagenesis, MS-based succinylation detection, succinyl-CoA synthetase activity assays, and SIRT5 overexpression rescue in AP models","pmids":["39643219"],"confidence":"Medium","gaps":["Whether K118 succinylation feedback operates under physiological conditions or only in disease","Relevance of this mechanism to SUCLA2 deficiency disease not tested"]},{"year":2025,"claim":"ERK2-mediated phosphorylation of SUCLA2 at S124 followed by PIN1 isomerization was shown to enable SUCLA2-OXCT1 interaction and OXCT1 K421 succinylation, linking SUCLA2 scaffold function to ketolysis activation and HCC tumor growth — expanding the phosphorylation-regulated scaffold paradigm to a second kinase and substrate.","evidence":"Co-IP, S124A/D and K421R mutagenesis, in vitro succinylation, PIN1 interaction studies, and mouse HCC tumor models","pmids":["39862868"],"confidence":"High","gaps":["Whether additional kinases beyond p38 and ERK2 regulate SUCLA2 scaffold interactions","Structural model of the SUCLA2-OXCT1 complex not available"]},{"year":2025,"claim":"Placing SUCLA2 in a glutaminolysis/AMPK/SUCLA2/succinate/IL-1β axis in adipose tissue macrophages revealed a non-canonical role for SUCLA2 enzymatic activity in inflammatory signaling and obesity.","evidence":"siRNA knockdown of SUCLA2 in mice, myeloid AMPK knockout, IL-1β neutralization, phosphorylation analysis, and metabolic phenotyping","pmids":["39966410"],"confidence":"Medium","gaps":["The specific AMPK phosphorylation site on SUCLA2 and its relationship to the p38/ERK2 sites not defined","Relative contribution of SUCLA2 enzymatic vs. scaffold function in macrophages not tested"]},{"year":2025,"claim":"Demonstrating that SUCLA2 negatively regulates SHMT2 succinylation to inhibit ferroptosis in renal fibrosis extended the scaffold-succinylation paradigm to a third target enzyme and a new cellular process.","evidence":"AAV-mediated SUCLA2 overexpression in mouse kidneys, SHMT2 siRNA epistasis, succinylation profiling, ferroptosis assays","pmids":["41359112"],"confidence":"Medium","gaps":["Whether SUCLA2-SHMT2 interaction is direct or indirect not confirmed by reciprocal pulldown","The succinylation site(s) on SHMT2 regulated by SUCLA2 not mapped"]},{"year":2026,"claim":"Using sucla2-knockout zebrafish, NAD+ depletion was identified as a key downstream consequence of succinylation-driven pathology, and NAD+ precursor supplementation rescued bioenergetics in a SIRT5-dependent manner, identifying a potential therapeutic axis.","evidence":"sucla2-/- zebrafish with behavioral, NAD+ metabolite, and SIRT5 genetic/pharmacologic rescue experiments","pmids":["41574612"],"confidence":"Medium","gaps":["Mechanism of succinylation-driven NAD+ consumption not molecularly defined","Whether NAD+ supplementation translates to mammalian SUCLA2-deficiency models not tested"]},{"year":null,"claim":"A unified structural and quantitative model explaining how SUCLA2 selects among multiple protein targets for succinylation regulation, and how its enzymatic and scaffold functions are coordinately controlled, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal structure of SUCLA2 in complex with any of its non-canonical partners (GLS, OXCT1, SHMT2, ALAS2)","Relative in vivo contribution of SUCLA2 scaffold vs. enzymatic function to disease not dissected","Whether all three phosphorylation events (S79, S124, AMPK site) are independent or competitive is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,6,7,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,9]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5,6,7,12]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,6,7,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,6,11,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,8]}],"complexes":["succinyl-CoA synthetase (ADP-forming)"],"partners":["SUCLG1","GLS","OXCT1","SHMT2","ALAS2","SIRT5","PIN1"],"other_free_text":[]},"mechanistic_narrative":"SUCLA2 encodes the ADP-forming β-subunit of mitochondrial succinyl-CoA synthetase (succinyl-CoA ligase), a TCA cycle enzyme that catalyzes the reversible conversion of succinyl-CoA to succinate with concomitant substrate-level phosphorylation of ADP [PMID:17287286]. Beyond its canonical metabolic role, SUCLA2 functions as a key regulator of protein succinylation: it physically associates with substrate proteins including GLS, OXCT1, SHMT2, and ALAS2, and signal-dependent phosphorylation of SUCLA2 by p38 (S79) or ERK2 (S124) modulates these interactions to control local succinyl-CoA availability and target-specific succinylation, thereby governing glutaminolysis, ketolysis, ferroptosis resistance, and heme biosynthesis [PMID:33991485, PMID:39862868, PMID:41359112, PMID:22740690]. Loss-of-function mutations in SUCLA2 cause succinyl-CoA accumulation, global protein hypersuccinylation, NAD+ depletion, and mtDNA depletion, resulting in autosomal recessive mitochondrial DNA depletion syndrome with encephalomyopathy and methylmalonic aciduria, a phenotype partially rescued by SIRT5-mediated desuccinylation or NAD+ precursor supplementation [PMID:33230181, PMID:17287286, PMID:41574612]. AMPK-mediated phosphorylation of SUCLA2 in macrophages links its enzymatic activity to succinate-driven inflammatory signaling and IL-1β production in obesity [PMID:39966410]."},"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":161,"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":154,"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":"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":"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":67,"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":"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":"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":19,"is_preprint":false},{"pmid":"24085565","id":"PMC_24085565","title":"Exclusive neuronal expression of SUCLA2 in the human brain.","date":"2013","source":"Brain structure & function","url":"https://pubmed.ncbi.nlm.nih.gov/24085565","citation_count":18,"is_preprint":false},{"pmid":"24659738","id":"PMC_24659738","title":"A novel SUCLA2 mutation in a Portuguese child associated with \"mild\" methylmalonic aciduria.","date":"2014","source":"Journal of child neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24659738","citation_count":17,"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":16,"is_preprint":false},{"pmid":"25370487","id":"PMC_25370487","title":"Localization of SUCLA2 and SUCLG2 subunits of succinyl CoA ligase within the cerebral cortex suggests the absence of matrix substrate-level phosphorylation in glial cells of the human brain.","date":"2014","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/25370487","citation_count":14,"is_preprint":false},{"pmid":"27651038","id":"PMC_27651038","title":"A Novel SUCLA2 Mutation Presenting as a Complex Childhood Movement Disorder.","date":"2016","source":"Journal of child 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":"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":"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":"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":"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":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":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":"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":"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":17606,"output_tokens":3705,"usd":0.054197},"stage2":{"model":"claude-opus-4-6","input_tokens":7118,"output_tokens":3471,"usd":0.183548},"total_usd":0.237745,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"SUCLA2 acts as a regulator of GLS (kidney-type glutaminase) succinylation: under oxidative stress, p38 MAPK phosphorylates SUCLA2 at S79, causing SUCLA2 to dissociate from GLS, which leads to enhanced GLS K311 succinylation, GLS oligomerization, and increased GLS activity, thereby boosting glutaminolysis and NADPH/glutathione production to counteract oxidative stress.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (S79A/D, K311R), in vitro succinylation assay, mouse tumor xenograft models, mass spectrometry\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including mutagenesis, biochemical assays, and in vivo validation in single highly-cited study\",\n      \"pmids\": [\"33991485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Upon IGF1 stimulation, ERK2 phosphorylates SUCLA2 at S124, followed by PIN1-mediated cis-trans isomerization of SUCLA2, enabling SUCLA2 to interact with OXCT1 (3-oxoacid CoA-transferase 1). SUCLA2-associated with OXCT1 generates succinyl-CoA, which directly succinylates OXCT1 at K421, activating OXCT1 and promoting ketolysis and HCC tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (S124A/D, K421R), in vitro succinylation assay, mouse tumor models, mass spectrometry\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including mutagenesis, biochemical reconstitution, and in vivo tumor models\",\n      \"pmids\": [\"39862868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss-of-function mutations in SUCLA2 cause succinyl-CoA accumulation and global protein hyper-succinylation across cellular compartments in patient-derived fibroblasts and myotubes; SIRT5 gain-of-function reduces global protein succinylation and improves survival in a zebrafish model of SCL deficiency, establishing succinyl-CoA-driven protein succinylation as a pathomechanism.\",\n      \"method\": \"Mass spectrometry quantification of ~1,000 succinylation sites, SIRT5 gain-of-function in zebrafish model, patient-derived fibroblasts and myotubes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — proteome-wide MS quantification combined with genetic rescue in zebrafish model, moderate evidence from a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33230181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SUCLA2 (β-subunit of succinyl-CoA synthetase) physically binds to ALAS2 (erythroid aminolevulinic acid synthase) via ALAS2's carboxyl-terminal region; XLSA mutations in ALAS2 exon 11 (p.Met567Val, p.Ser568Gly) and a truncation (p.Phe557Ter) abolish binding to SUCLA2 without affecting intrinsic ALAS2 enzymatic activity, implicating the ALAS2-SUCLA2 complex in regulation of erythroid heme biosynthesis.\",\n      \"method\": \"SUCLA2 affinity column pulldown with recombinant mutant ALAS2 proteins, enzymatic kinetics assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — affinity pulldown with multiple mutant proteins and kinetic characterization, single lab\",\n      \"pmids\": [\"22740690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SUCLG2 (GDP-forming β-subunit isoform) compensates for SUCLA2 deficiency in fibroblasts; knockdown of SUCLG2 by shRNA in SUCLA2-deficient patient fibroblasts causes significant decreases in mtDNA content, NDPK activity, and cytochrome c oxidase activity, establishing that mitochondrial NDPK association is linked to mtDNA maintenance and that SUCLG2 is more critical than SUCLA2 for mtDNA maintenance in fibroblasts.\",\n      \"method\": \"shRNA knockdown of SUCLG2 in patient-derived fibroblasts, quantification of mtDNA, NDPK activity assay, cytochrome c oxidase activity assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown with multiple enzymatic readouts in patient-derived cells, single lab\",\n      \"pmids\": [\"21295139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SUCLA2 protein (A-SUCL-β) is expressed exclusively in neurons in the human cerebral cortex, co-localizing >99% with mitochondrial F0-F1 ATP synthase d-subunit; it is absent in GFAP- and S100-positive astrocytes and confirmed absent by both immunofluorescence and in situ hybridization. Glial cells lack both SUCLA2 and SUCLG2, consistent with alternative metabolic pathways (GABA shunt, ketone body metabolism) in glia.\",\n      \"method\": \"Immunofluorescence with cell-type markers, in situ hybridization, Western blotting, patient fibroblast negative control (complete SUCLA2 deletion)\",\n      \"journal\": \"Brain structure & function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct immunohistochemistry and ISH with orthogonal markers and patient-derived negative control, single lab\",\n      \"pmids\": [\"24085565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mutations in SUCLA2 (encoding the ADP-forming β-subunit of succinyl-CoA ligase) cause accumulation of succinyl-CoA, which inhibits conversion of methylmalonyl-CoA to succinyl-CoA and leads to elevated methylmalonic acid; this is accompanied by mtDNA depletion, establishing SUCLA2 as essential for TCA cycle function and mtDNA maintenance.\",\n      \"method\": \"Genetic analysis, homozygosity mapping, metabolite profiling (urine MMA, plasma lactate, carnitine esters), protein-level confirmation in patient samples\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and biochemical characterization in multiple patient cohorts, replicated across two independent cohorts (PMID 17287286 and 17301081)\",\n      \"pmids\": [\"17287286\", \"17301081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT5 downregulation leads to SUCLA2 hypersuccinylation at K118, which inhibits succinyl-CoA synthetase activity, causing a vicious cycle of succinyl-CoA accumulation and further SUCLA2 succinylation; SIRT5 overexpression or SUCLA2 knockdown attenuates TCA cycle dysregulation, protein hypersuccinylation, and mitochondrial damage in acute pancreatitis models.\",\n      \"method\": \"Colorimetric succinyl-CoA synthetase activity assay, mass spectrometry, site-directed mutagenesis (K118R), adenovirus-mediated SIRT5 overexpression, in vitro and in vivo AP models\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis, MS, enzymatic activity assay, and genetic rescue, single lab with moderate evidence\",\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 β-subunit, thereby activating succinyl-CoA synthetase and leading to overproduction of succinate and IL-1β; SUCLA2 knockdown by siRNA reduces obesity in HFD-fed mice, placing SUCLA2 in a glutaminolysis/AMPK/SUCLA2/IL-1β inflammatory axis.\",\n      \"method\": \"siRNA knockdown of SUCLA2 in mice, AMPK genetic knockout in myeloid cells, IL-1β neutralization, phosphorylation analysis, metabolic phenotyping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacologic interventions with mechanistic pathway placement, single lab\",\n      \"pmids\": [\"39966410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SUCLA2 negatively regulates lysine succinylation of SHMT2; overexpression of SUCLA2 reduces succinyl-CoA levels and SHMT2 succinylation, thereby inhibiting ferroptosis in Ang II-induced renal fibrosis models; SIRT5-mediated desuccinylation of SHMT2 mimics this effect, and the anti-ferroptotic effect of SUCLA2 overexpression is reversed by SHMT2 silencing.\",\n      \"method\": \"SUCLA2 overexpression via AAV in mouse kidneys, SHMT2 siRNA knockdown, succinylation profiling, ferroptosis assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic gain/loss-of-function with epistasis rescue experiment, single lab\",\n      \"pmids\": [\"41359112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Knockdown of Sucla2 in mouse GC2 spermatocytes decreases cell viability, mitochondrial membrane potential, ATP production, and Bcl2 expression, and increases ROS and apoptosis, establishing a direct role for SUCLA2 in maintaining mitochondrial function and cell survival in spermatocytes.\",\n      \"method\": \"siRNA knockdown in GC2 cells, flow cytometry (MMP, apoptosis, ROS), ATP luminometric assay, Western blot\",\n      \"journal\": \"Folia histochemica et cytobiologica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method per endpoint, single lab, no pathway placement beyond mitochondrial dysfunction\",\n      \"pmids\": [\"27766610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In sucla2-/- zebrafish, excess succinyl-CoA drives bulk protein succinylation that consumes NAD+, propagating mitochondrial respiratory defects and locomotor impairment; NAD+ precursor supplementation restores NAD+ levels and requires the desuccinylase Sirt5 to improve oxidative metabolism and survival, mechanistically linking succinylation-driven NAD+ depletion to mitochondrial bioenergetics failure.\",\n      \"method\": \"sucla2-/- zebrafish model, behavioral locomotor assays, NAD+ metabolite quantification, Sirt5 genetic manipulation, NAD+ precursor supplementation (nicotinamide, nicotinamide riboside)\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic model with pharmacological and genetic rescue, multiple readouts, single lab\",\n      \"pmids\": [\"41574612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Muscle-specific conditional knockout of Sucla2 in mice (using HSA-Cre) yields mitochondrial myopathy with reduced body weight, grip strength, and exercise capacity; soleus muscles show 40% less specific tetanic force and a ~2-fold increase in Type 1 myosin heavy chain fibers and mitochondrial content, while EDL muscles are comparatively unaffected, establishing muscle-type-specific consequences of SUCLA2 loss.\",\n      \"method\": \"Cre-lox conditional knockout, ex vivo contractility measurements, fiber-type immunostaining, COX/SDH histochemistry, RT-qPCR, Western blot, serum metabolite mass spectrometry\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with multiple orthogonal phenotypic readouts, single lab\",\n      \"pmids\": [\"39482887\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SUCLA2 encodes the ADP-forming β-subunit of the mitochondrial succinyl-CoA synthetase (ligase), which catalyzes reversible conversion of succinyl-CoA to succinate with coupled ADP phosphorylation in the TCA cycle; beyond its canonical enzymatic role, SUCLA2 acts as a direct regulator of protein succinylation by controlling local succinyl-CoA availability — it physically associates with substrate enzymes (GLS, OXCT1, SHMT2) and its p38/ERK2-mediated phosphorylation (at S79 or S124) governs these interactions, modulating succinylation-dependent activation or inhibition of target enzymes in cancer metabolism, ketolysis, and stress responses; loss of SUCLA2 causes succinyl-CoA accumulation, global protein hyper-succinylation, NAD+ depletion, and mtDNA depletion, explaining the encephalomyopathy and mitochondrial disease phenotypes observed in patients.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SUCLA2 encodes the ADP-forming β-subunit of mitochondrial succinyl-CoA synthetase (succinyl-CoA ligase), a TCA cycle enzyme that catalyzes the reversible conversion of succinyl-CoA to succinate with concomitant substrate-level phosphorylation of ADP [PMID:17287286]. Beyond its canonical metabolic role, SUCLA2 functions as a key regulator of protein succinylation: it physically associates with substrate proteins including GLS, OXCT1, SHMT2, and ALAS2, and signal-dependent phosphorylation of SUCLA2 by p38 (S79) or ERK2 (S124) modulates these interactions to control local succinyl-CoA availability and target-specific succinylation, thereby governing glutaminolysis, ketolysis, ferroptosis resistance, and heme biosynthesis [PMID:33991485, PMID:39862868, PMID:41359112, PMID:22740690]. Loss-of-function mutations in SUCLA2 cause succinyl-CoA accumulation, global protein hypersuccinylation, NAD+ depletion, and mtDNA depletion, resulting in autosomal recessive mitochondrial DNA depletion syndrome with encephalomyopathy and methylmalonic aciduria, a phenotype partially rescued by SIRT5-mediated desuccinylation or NAD+ precursor supplementation [PMID:33230181, PMID:17287286, PMID:41574612]. AMPK-mediated phosphorylation of SUCLA2 in macrophages links its enzymatic activity to succinate-driven inflammatory signaling and IL-1β production in obesity [PMID:39966410].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing SUCLA2 as an essential TCA cycle enzyme whose loss causes mtDNA depletion and methylmalonic aciduria resolved the genetic basis of a mitochondrial encephalomyopathy.\",\n      \"evidence\": \"Homozygosity mapping, mutation identification, and metabolite profiling in multiple patient cohorts\",\n      \"pmids\": [\"17287286\", \"17301081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking succinyl-CoA ligase deficiency to mtDNA depletion was not established\",\n        \"No direct enzymatic activity measurement in patient tissues\",\n        \"Tissue-specific consequences of SUCLA2 loss not explored\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that SUCLG2 compensates for SUCLA2 loss in fibroblasts and that mitochondrial NDPK association is linked to mtDNA maintenance clarified why mtDNA depletion occurs in SUCLA2-deficient tissues.\",\n      \"evidence\": \"shRNA knockdown of SUCLG2 in SUCLA2-deficient patient fibroblasts with mtDNA, NDPK, and cytochrome c oxidase quantification\",\n      \"pmids\": [\"21295139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"NDPK-mtDNA maintenance mechanism not molecularly dissected\",\n        \"Compensation dynamics not tested in neuronal or muscle tissue where disease manifests\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The discovery that SUCLA2 physically binds ALAS2 and that XLSA mutations disrupt this interaction without affecting ALAS2 catalysis revealed SUCLA2 as a scaffold for substrate channeling in heme biosynthesis.\",\n      \"evidence\": \"Affinity pulldown of recombinant wild-type and mutant ALAS2 proteins on SUCLA2 columns with kinetic assays\",\n      \"pmids\": [\"22740690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of SUCLA2-ALAS2 disruption on heme synthesis rates not measured in cells\",\n        \"No reciprocal Co-IP or in vivo validation\",\n        \"Structural basis of the interaction unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that SUCLA2 is expressed exclusively in neurons (not glia) in human cortex explained why SUCLA2 deficiency preferentially causes encephalopathy and why glial cells rely on alternative metabolic pathways.\",\n      \"evidence\": \"Immunofluorescence co-localization with neuronal and glial markers, in situ hybridization, and SUCLA2-null patient fibroblast negative control in human cortex\",\n      \"pmids\": [\"24085565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Glial metabolic compensation not functionally tested\",\n        \"Expression pattern not confirmed across brain regions beyond cortex\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Proteome-wide succinylation profiling of SUCLA2-deficient cells and rescue by SIRT5 gain-of-function in zebrafish established protein hypersuccinylation as a direct pathomechanism rather than simply a biomarker of disease.\",\n      \"evidence\": \"Quantitative MS of ~1,000 succinylation sites in patient fibroblasts/myotubes; SIRT5 gain-of-function rescue in zebrafish SCL deficiency model\",\n      \"pmids\": [\"33230181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific succinylation targets driving pathology not identified\",\n        \"Whether succinylation or succinyl-CoA accumulation per se is more pathogenic remained unclear\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that p38-mediated phosphorylation of SUCLA2 at S79 controls its dissociation from GLS and thereby regulates GLS succinylation and glutaminolysis transformed the view of SUCLA2 from a passive metabolic enzyme to an active, signal-responsive regulator of protein succinylation.\",\n      \"evidence\": \"Co-IP, S79A/D and K311R mutagenesis, in vitro succinylation assay, and mouse tumor xenograft models\",\n      \"pmids\": [\"33991485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether SUCLA2 scaffold function is general across all succinylation substrates or target-specific\",\n        \"Structural basis of phosphorylation-induced dissociation not determined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Conditional muscle-specific Sucla2 knockout revealed that slow-twitch (soleus) fibers are selectively vulnerable to SUCLA2 loss, establishing muscle-type-specific bioenergetic consequences and fiber-type remodeling as features of the myopathy.\",\n      \"evidence\": \"Cre-lox conditional knockout (HSA-Cre), ex vivo contractility, fiber-type immunostaining, and serum metabolomics in mice\",\n      \"pmids\": [\"39482887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular basis of differential vulnerability between soleus and EDL not defined\",\n        \"Contribution of protein succinylation vs. bioenergetic deficit to myopathy not dissected\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of SUCLA2 K118 as a feedback succinylation site inhibiting its own enzymatic activity, regulated by SIRT5, established a vicious-cycle mechanism in which SUCLA2 inactivation amplifies succinyl-CoA accumulation in acute pancreatitis.\",\n      \"evidence\": \"K118R mutagenesis, MS-based succinylation detection, succinyl-CoA synthetase activity assays, and SIRT5 overexpression rescue in AP models\",\n      \"pmids\": [\"39643219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether K118 succinylation feedback operates under physiological conditions or only in disease\",\n        \"Relevance of this mechanism to SUCLA2 deficiency disease not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ERK2-mediated phosphorylation of SUCLA2 at S124 followed by PIN1 isomerization was shown to enable SUCLA2-OXCT1 interaction and OXCT1 K421 succinylation, linking SUCLA2 scaffold function to ketolysis activation and HCC tumor growth — expanding the phosphorylation-regulated scaffold paradigm to a second kinase and substrate.\",\n      \"evidence\": \"Co-IP, S124A/D and K421R mutagenesis, in vitro succinylation, PIN1 interaction studies, and mouse HCC tumor models\",\n      \"pmids\": [\"39862868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether additional kinases beyond p38 and ERK2 regulate SUCLA2 scaffold interactions\",\n        \"Structural model of the SUCLA2-OXCT1 complex not available\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placing SUCLA2 in a glutaminolysis/AMPK/SUCLA2/succinate/IL-1β axis in adipose tissue macrophages revealed a non-canonical role for SUCLA2 enzymatic activity in inflammatory signaling and obesity.\",\n      \"evidence\": \"siRNA knockdown of SUCLA2 in mice, myeloid AMPK knockout, IL-1β neutralization, phosphorylation analysis, and metabolic phenotyping\",\n      \"pmids\": [\"39966410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The specific AMPK phosphorylation site on SUCLA2 and its relationship to the p38/ERK2 sites not defined\",\n        \"Relative contribution of SUCLA2 enzymatic vs. scaffold function in macrophages not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that SUCLA2 negatively regulates SHMT2 succinylation to inhibit ferroptosis in renal fibrosis extended the scaffold-succinylation paradigm to a third target enzyme and a new cellular process.\",\n      \"evidence\": \"AAV-mediated SUCLA2 overexpression in mouse kidneys, SHMT2 siRNA epistasis, succinylation profiling, ferroptosis assays\",\n      \"pmids\": [\"41359112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SUCLA2-SHMT2 interaction is direct or indirect not confirmed by reciprocal pulldown\",\n        \"The succinylation site(s) on SHMT2 regulated by SUCLA2 not mapped\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Using sucla2-knockout zebrafish, NAD+ depletion was identified as a key downstream consequence of succinylation-driven pathology, and NAD+ precursor supplementation rescued bioenergetics in a SIRT5-dependent manner, identifying a potential therapeutic axis.\",\n      \"evidence\": \"sucla2-/- zebrafish with behavioral, NAD+ metabolite, and SIRT5 genetic/pharmacologic rescue experiments\",\n      \"pmids\": [\"41574612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of succinylation-driven NAD+ consumption not molecularly defined\",\n        \"Whether NAD+ supplementation translates to mammalian SUCLA2-deficiency models not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural and quantitative model explaining how SUCLA2 selects among multiple protein targets for succinylation regulation, and how its enzymatic and scaffold functions are coordinately controlled, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal structure of SUCLA2 in complex with any of its non-canonical partners (GLS, OXCT1, SHMT2, ALAS2)\",\n        \"Relative in vivo contribution of SUCLA2 scaffold vs. enzymatic function to disease not dissected\",\n        \"Whether all three phosphorylation events (S79, S124, AMPK site) are independent or competitive is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 6, 7, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5, 6, 7, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 6, 7, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 6, 11, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 8]}\n    ],\n    \"complexes\": [\n      \"succinyl-CoA synthetase (ADP-forming)\"\n    ],\n    \"partners\": [\n      \"SUCLG1\",\n      \"GLS\",\n      \"OXCT1\",\n      \"SHMT2\",\n      \"ALAS2\",\n      \"SIRT5\",\n      \"PIN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}