Affinage

SUCLA2

Succinate--CoA ligase [ADP-forming] subunit beta, mitochondrial · UniProt Q9P2R7

Length
463 aa
Mass
50.3 kDa
Annotated
2026-04-28
30 papers in source corpus 14 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2007 Medium

    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

    PMID:17287286 PMID:17301081

    Open questions at the time
    • 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
  2. 2011 Medium

    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

    PMID:21295139

    Open questions at the time
    • NDPK-mtDNA maintenance mechanism not molecularly dissected
    • Compensation dynamics not tested in neuronal or muscle tissue where disease manifests
  3. 2012 Medium

    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

    PMID:22740690

    Open questions at the time
    • 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
  4. 2013 Medium

    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

    PMID:24085565

    Open questions at the time
    • Glial metabolic compensation not functionally tested
    • Expression pattern not confirmed across brain regions beyond cortex
  5. 2020 High

    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

    PMID:33230181

    Open questions at the time
    • Specific succinylation targets driving pathology not identified
    • Whether succinylation or succinyl-CoA accumulation per se is more pathogenic remained unclear
  6. 2021 High

    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

    PMID:33991485

    Open questions at the time
    • Whether SUCLA2 scaffold function is general across all succinylation substrates or target-specific
    • Structural basis of phosphorylation-induced dissociation not determined
  7. 2024 Medium

    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

    PMID:39482887

    Open questions at the time
    • Molecular basis of differential vulnerability between soleus and EDL not defined
    • Contribution of protein succinylation vs. bioenergetic deficit to myopathy not dissected
  8. 2024 Medium

    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

    PMID:39643219

    Open questions at the time
    • Whether K118 succinylation feedback operates under physiological conditions or only in disease
    • Relevance of this mechanism to SUCLA2 deficiency disease not tested
  9. 2025 High

    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

    PMID:39862868

    Open questions at the time
    • Whether additional kinases beyond p38 and ERK2 regulate SUCLA2 scaffold interactions
    • Structural model of the SUCLA2-OXCT1 complex not available
  10. 2025 Medium

    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

    PMID:39966410

    Open questions at the time
    • 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
  11. 2025 Medium

    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

    PMID:41359112

    Open questions at the time
    • Whether SUCLA2-SHMT2 interaction is direct or indirect not confirmed by reciprocal pulldown
    • The succinylation site(s) on SHMT2 regulated by SUCLA2 not mapped
  12. 2026 Medium

    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

    PMID:41574612

    Open questions at the time
    • Mechanism of succinylation-driven NAD+ consumption not molecularly defined
    • Whether NAD+ supplementation translates to mammalian SUCLA2-deficiency models not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 5 GO:0060090 molecular adaptor activity 4
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2
Partners
ALAS2GLSOXCT1PIN1SHMT2SIRT5SUCLG1
Complex memberships
succinyl-CoA synthetase (ADP-forming)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 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. Co-immunoprecipitation, site-directed mutagenesis (S79A/D, K311R), in vitro succinylation assay, mouse tumor xenograft models, mass spectrometry Molecular cell High 33991485
2025 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. Co-immunoprecipitation, site-directed mutagenesis (S124A/D, K421R), in vitro succinylation assay, mouse tumor models, mass spectrometry Molecular cell High 39862868
2020 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. Mass spectrometry quantification of ~1,000 succinylation sites, SIRT5 gain-of-function in zebrafish model, patient-derived fibroblasts and myotubes Nature communications High 33230181
2012 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. SUCLA2 affinity column pulldown with recombinant mutant ALAS2 proteins, enzymatic kinetics assays The Journal of biological chemistry Medium 22740690
2011 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. shRNA knockdown of SUCLG2 in patient-derived fibroblasts, quantification of mtDNA, NDPK activity assay, cytochrome c oxidase activity assay Biochimica et biophysica acta Medium 21295139
2013 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. Immunofluorescence with cell-type markers, in situ hybridization, Western blotting, patient fibroblast negative control (complete SUCLA2 deletion) Brain structure & function Medium 24085565
2007 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. Genetic analysis, homozygosity mapping, metabolite profiling (urine MMA, plasma lactate, carnitine esters), protein-level confirmation in patient samples Brain : a journal of neurology Medium 17287286 17301081
2024 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. Colorimetric succinyl-CoA synthetase activity assay, mass spectrometry, site-directed mutagenesis (K118R), adenovirus-mediated SIRT5 overexpression, in vitro and in vivo AP models Biochimica et biophysica acta. Molecular basis of disease Medium 39643219
2025 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. siRNA knockdown of SUCLA2 in mice, AMPK genetic knockout in myeloid cells, IL-1β neutralization, phosphorylation analysis, metabolic phenotyping Nature communications Medium 39966410
2025 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. SUCLA2 overexpression via AAV in mouse kidneys, SHMT2 siRNA knockdown, succinylation profiling, ferroptosis assays FASEB journal Medium 41359112
2016 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. siRNA knockdown in GC2 cells, flow cytometry (MMP, apoptosis, ROS), ATP luminometric assay, Western blot Folia histochemica et cytobiologica Low 27766610
2026 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. sucla2-/- zebrafish model, behavioral locomotor assays, NAD+ metabolite quantification, Sirt5 genetic manipulation, NAD+ precursor supplementation (nicotinamide, nicotinamide riboside) JCI insight Medium 41574612
2024 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. Cre-lox conditional knockout, ex vivo contractility measurements, fiber-type immunostaining, COX/SDH histochemistry, RT-qPCR, Western blot, serum metabolite mass spectrometry Journal of cachexia, sarcopenia and muscle Medium 39482887

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 SUCLA2-coupled regulation of GLS succinylation and activity counteracts oxidative stress in tumor cells. Molecular cell 161 33991485
2007 SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. Brain : a journal of neurology 154 17301081
2007 Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations. Brain : a journal of neurology 146 17287286
2015 Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients. Journal of inherited metabolic disease 71 26475597
2020 SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease. Nature communications 67 33230181
2011 The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion. Biochimica et biophysica acta 48 21295139
2012 X-linked sideroblastic anemia due to carboxyl-terminal ALAS2 mutations that cause loss of binding to the β-subunit of succinyl-CoA synthetase (SUCLA2). The Journal of biological chemistry 42 22740690
2009 Dystonia and deafness due to SUCLA2 defect; Clinical course and biochemical markers in 16 children. Mitochondrion 41 19666145
2012 A novel homozygous mutation in SUCLA2 gene identified by exome sequencing. Molecular genetics and metabolism 36 23010432
2016 Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion. Molecular genetics and metabolism 22 27913098
2014 Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion. European journal of human genetics : EJHG 21 24986829
2025 OXCT1 succinylation and activation by SUCLA2 promotes ketolysis and liver tumor growth. Molecular cell 19 39862868
2013 Exclusive neuronal expression of SUCLA2 in the human brain. Brain structure & function 18 24085565
2014 A novel SUCLA2 mutation in a Portuguese child associated with "mild" methylmalonic aciduria. Journal of child neurology 17 24659738
2025 Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK. Nature communications 16 39966410
2016 A Novel SUCLA2 Mutation Presenting as a Complex Childhood Movement Disorder. Journal of child neurology 14 27651038
2014 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. Journal of bioenergetics and biomembranes 14 25370487
2020 Pharmacologically targetable vulnerability in prostate cancer carrying RB1-SUCLA2 deletion. Oncogene 13 32694611
2016 Influences of XDH genotype by gene-gene interactions with SUCLA2 for thiopurine-induced leukopenia in Korean patients with Crohn's disease. Scandinavian journal of gastroenterology 9 26863601
2015 SUCLA2 Deficiency: A Deafness-Dystonia Syndrome with Distinctive Metabolic Findings (Report of a New Patient and Review of the Literature). JIMD reports 8 26409464
2014 [SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome: a case report and review of literature]. Zhonghua er ke za zhi = Chinese journal of pediatrics 8 25582465
2020 SUCLA2 Arg407Trp mutation can cause a nonprogressive movement disorder - deafness syndrome. Annals of clinical and translational neurology 6 33231368
2024 Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes. Journal of cachexia, sarcopenia and muscle 3 39482887
2024 SIRT5 mediated succinylation of SUCLA2 regulates TCA cycle dysfunction and mitochondrial damage in pancreatic acinar cells in acute pancreatitis. Biochimica et biophysica acta. Molecular basis of disease 3 39643219
2016 Novel mutation in SUCLA2 identified on sequencing analysis. Pediatrics international : official journal of the Japan Pediatric Society 3 26952923
2016 Knockdown of Sucla2 decreases the viability of mouse spermatocytes by inducing apoptosis through injury of the mitochondrial function of cells. Folia histochemica et cytobiologica 3 27766610
2026 NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations. JCI insight 0 41574612
2025 SUCLA2 Inhibited Lysine Succinylation of SHMT2 to Suppress Ferroptosis and Renal Interstitial Fibrosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41359112
2024 Two novel SUCLA2 variants cause mitochondrial DNA depletion syndrome, type 5 in two siblings. Frontiers in neurology 0 39070054
2017 Co-occurring Down syndrome and SUCLA2-related mitochondrial depletion syndrome. American journal of medical genetics. Part A 0 28749033