Affinage

SUCLA2

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

Length
463 aa
Mass
50.3 kDa
Annotated
2026-06-10
30 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2011 Medium

    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

    PMID:21295139

    Open questions at the time
    • 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
  2. 2012 Medium

    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

    PMID:22740690

    Open questions at the time
    • No structural model of the ALAS2–SUCLA2 interface
    • Whether succinyl-CoA channeling rather than binding per se drives the effect not tested
  3. 2013 Medium

    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

    PMID:24085565

    Open questions at the time
    • Does not establish why neurons cannot compensate via SUCLG2
    • Single-region cortical sampling
  4. 2014 Medium

    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

    PMID:25370487

    Open questions at the time
    • Functional consequence of vascular-restricted SUCLG2 not tested
    • No quantitative comparison of flux contributions
  5. 2020 High

    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

    PMID:33230181

    Open questions at the time
    • Which hyper-succinylated targets are pathogenically decisive not pinpointed
    • Compartment-specific succinyl-CoA dynamics not directly measured
  6. 2021 High

    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

    PMID:33991485

    Open questions at the time
    • Whether dissociation increases bulk or only GLS-local succinyl-CoA not distinguished
    • Generality of the dissociation switch beyond oxidative stress unclear
  7. 2024 Medium

    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

    PMID:39643219

    Open questions at the time
    • Stoichiometry and kinetics of K118 succinylation on activity not quantified
    • Direct link from CYC1 succinylation to cGAS-STING activation indirect
  8. 2024 Medium

    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

    PMID:39482887

    Open questions at the time
    • Molecular basis of soleus-versus-EDL vulnerability not defined
    • Succinylation status of muscle proteins not profiled
  9. 2025 High

    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

    PMID:39862868

    Open questions at the time
    • 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
  10. 2025 Medium

    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

    PMID:39966410

    Open questions at the time
    • AMPK phosphorylation sites on SUCLA2 not mapped
    • Direct demonstration that succinate alone drives IL-1β incomplete
  11. 2026 Medium

    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

    PMID:41574612

    Open questions at the time
    • Translation of NAD+ precursor benefit to mammalian/patient settings untested
    • Quantitative contribution of succinylation to NAD+ consumption not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0016740 transferase activity 2 GO:0016874 ligase activity 2
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3
Partners
ALAS2GLSOXCT1SIRT5
Complex memberships
succinyl-CoA synthetase (SCS)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 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. 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 Molecular cell High 33991485
2025 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. 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 Molecular cell High 39862868
2020 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. Mass spectrometry quantification of succinylation sites in patient-derived fibroblasts and myotubes, zebrafish sucla2 KO model with SIRT5 gain-of-function rescue, metabolite measurements Nature communications High 33230181
2011 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. shRNA knockdown of SUCLG2 in patient and control fibroblasts, mtDNA quantification, NDPK activity assay, cytochrome c oxidase activity assay Biochimica et biophysica acta Medium 21295139
2012 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. SUCLA2 affinity column pulldown with recombinant ALAS2 wild-type and mutant proteins, enzymatic activity and kinetics assays The Journal of biological chemistry Medium 22740690
2024 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. Colorimetric enzyme activity assays, mass spectrometry, site-directed mutagenesis (SUCLA2 K118), adenovirus-mediated SIRT5 overexpression, SUCLA2 knockdown, 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. 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. siRNA knockdown of SUCLA2 in mice, AMPKα myeloid cell knockout, IL-1β neutralization, metabolite measurements, phosphorylation analysis Nature communications Medium 39966410
2013 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. Immunofluorescence with cell-type markers on surgical human cortical tissue, in situ hybridization, Western blot, negative control using SUCLA2-null patient fibroblasts Brain structure & function Medium 24085565
2014 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. Double immunofluorescence with Iba1, myelin basic protein, mitotracker, GFAP, S100, and SUCLA2/SUCLG2 antibodies on surgical human cortical tissue and fibroblast cultures Journal of bioenergetics and biomembranes Medium 25370487
2024 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. 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 of cachexia, sarcopenia and muscle Medium 39482887
2026 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. Zebrafish sucla2 knockout model, NAD+ metabolite measurements, behavioral locomotor assays, Sirt5 genetic requirement testing, metabolomics JCI insight Medium 41574612
2016 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. siRNA knockdown in GC2 mouse spermatocyte cells, flow cytometry (MMP, apoptosis, ROS), luminometric ATP assay, Western blot (Bcl2), immunohistochemistry for localization in testis Folia histochemica et cytobiologica Low 27766610
2025 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. Adeno-associated virus-mediated SUCLA2 overexpression in mice, SHMT2 siRNA knockdown, succinylome analysis, metabolite measurements, ferroptosis markers FASEB journal Low 41359112

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 166 33991485
2007 SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. Brain : a journal of neurology 155 17301081
2007 Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations. Brain : a journal of neurology 146 17287286
2020 SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease. Nature communications 71 33230181
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
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
2025 OXCT1 succinylation and activation by SUCLA2 promotes ketolysis and liver tumor growth. Molecular cell 22 39862868
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 Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK. Nature communications 20 39966410
2014 A novel SUCLA2 mutation in a Portuguese child associated with "mild" methylmalonic aciduria. Journal of child neurology 18 24659738
2013 Exclusive neuronal expression of SUCLA2 in the human brain. Brain structure & function 18 24085565
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 4 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
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 2 41359112
2026 NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations. JCI insight 0 41574612
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

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