Affinage

SUCLG2

Succinate--CoA ligase [GDP-forming] subunit beta, mitochondrial · UniProt Q96I99

Round 2 corrected
Length
432 aa
Mass
46.5 kDa
Annotated
2026-04-28
41 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SUCLG2 encodes the GTP-specific beta subunit of mitochondrial succinyl-CoA ligase (succinate–CoA ligase, GDP-forming), which heterodimerizes with the SUCLG1 alpha subunit to catalyze the reversible conversion of succinyl-CoA to succinate coupled with substrate-level GTP synthesis in the tricarboxylic acid cycle (PMID:9765291, PMID:15234968). Beyond this core catalytic role, SUCLG2 is required for mitochondrial DNA maintenance through functional coupling with nucleoside diphosphate kinase, for proper assembly of succinate dehydrogenase (complex II), and for controlling the global protein succinylation landscape—its own stability being regulated by SIRT5-mediated desuccinylation at Lys93, which triggers TRIM21-dependent ubiquitination and lysosomal degradation (PMID:21295139, PMID:34415331, PMID:37904651). Correct mitochondrial localization of SUCLG2 depends on an intact SUCLG1 alpha subunit, and tissue-specific expression of SUCLG2 versus the ATP-forming SUCLA2 isoform tunes the balance between GTP- and ATP-generating substrate-level phosphorylation (PMID:30470562, PMID:15234968). Germline variants in SUCLG2 have been identified in pheochromocytoma/paraganglioma patients, where loss of SUCLG2 leads to defective complex II assembly, aberrant respiration, and succinate accumulation (PMID:34415331).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1998 High

    Identification of SUCLG2 as a distinct GTP-specific beta subunit established that two succinyl-CoA synthetase isoenzymes exist in multicellular eukaryotes, resolving why both GTP- and ATP-linked activities had been detected in mitochondria.

    Evidence RT-PCR cloning and sequence alignment across mammalian species

    PMID:9765291

    Open questions at the time
    • No crystal structure of the GDP-forming heterodimer
    • Relative catalytic parameters of SUCLG2- versus SUCLA2-containing holoenzymes not yet determined
  2. 2004 High

    Tissue-level profiling showed that the SUCLG2 (GDP-forming) and SUCLA2 (ADP-forming) isoforms are differentially expressed across mammalian organs, indicating that tissue-specific TCA cycle tuning is achieved through beta-subunit selection.

    Evidence Western blot, Northern blot, and enzymatic activity assays across mammalian tissues

    PMID:15234968

    Open questions at the time
    • Transcriptional regulators controlling isoform selection not identified
    • High-energy phosphate shuttling between matrix GTP and cytosolic ATP remained hypothetical
  3. 2011 High

    Knockdown of SUCLG2 revealed an unexpected extra-catalytic role: SUCLG2 is required for mtDNA maintenance through its association with mitochondrial NDPK, linking succinyl-CoA ligase deficiency to mtDNA depletion syndrome.

    Evidence shRNA knockdown in human fibroblasts with mtDNA quantification, NDPK activity assay, and cytochrome c oxidase activity measurement

    PMID:21295139

    Open questions at the time
    • Direct physical interaction between SUCLG2 and mitochondrial NDPK not structurally characterized
    • Whether the NDPK-coupling mechanism differs between SUCLG2 and SUCLA2 isoforms was not resolved
  4. 2014 Medium

    Subcellular imaging confirmed SUCLG2 resides in the mitochondrial network and demonstrated cell-type-specific expression in human brain, with SUCLG2 present in cerebrovascular cells but absent from glia.

    Evidence Double immunofluorescence confocal microscopy with MitoTracker co-localization and in situ hybridization in human cortical tissue

    PMID:25370487

    Open questions at the time
    • Functional consequence of glial absence of SUCLG2 not tested directly
    • Sub-mitochondrial localization (matrix vs. inner membrane association) not resolved
  5. 2018 High

    Analysis of a pathogenic SUCLG1 mutation showed that proper SUCLG1 is required for SUCLG2 mitochondrial targeting and protein stability, establishing the alpha subunit as a determinant of holoenzyme assembly and localization.

    Evidence Confocal triple-label immunocytochemistry, substrate-level phosphorylation assays, and mtDNA quantification in patient-derived fibroblasts

    PMID:30470562

    Open questions at the time
    • Whether mislocalized SUCLG2 is degraded by cytoplasmic quality control was not addressed
    • Import pathway elements mediating SUCLG2 mitochondrial targeting unknown
  6. 2022 High

    Discovery that SUCLG2 loss leads to defective SDH (complex II) assembly, aberrant respiration, and succinate accumulation expanded SUCLG2's role beyond the TCA cycle reaction itself and linked germline SUCLG2 variants to pheochromocytoma/paraganglioma.

    Evidence SUCLG2 ablation and re-expression in hPheo1 cells, SDHB immunoblot, respiratory assays, succinate measurement, and patient tumor genetic sequencing

    PMID:34415331

    Open questions at the time
    • Mechanism by which SUCLG2 supports SDHB stability or SDH assembly is unclear
    • Penetrance and genotype–phenotype correlation of SUCLG2 variants in PPGL not established in large cohorts
  7. 2023 High

    Succinylome profiling established SUCLG2 as a master regulator of mitochondrial protein succinylation, and identified a feedback loop in which SUCLG2 Lys93 succinylation stabilizes the protein while SIRT5-mediated desuccinylation triggers TRIM21-dependent ubiquitination and lysosomal degradation.

    Evidence Succinylome mass spectrometry, SUCLG2 deletion, K93 site-directed mutagenesis, Co-IP with TRIM21, ubiquitination assays, and lysosome inhibitor treatment in lung adenocarcinoma cells

    PMID:37904651

    Open questions at the time
    • Whether succinylation at K93 regulates catalytic activity in addition to stability is untested
    • Generalizability of SIRT5-TRIM21 axis beyond lung adenocarcinoma not confirmed
  8. 2023 Medium

    In regulatory dendritic cells, SUCLG2 suppresses NF-κB signaling by preventing succinylation of Lactb at K288, revealing an immunomodulatory function linked to succinylation control.

    Evidence siRNA knockdown with NF-κB signaling assays, succinylation site identification on Lactb, metabolomic and transcriptomic profiling, and T cell apoptosis functional assays

    PMID:37216870

    Open questions at the time
    • Whether SUCLG2 directly desuccinylates Lactb or acts indirectly through succinyl-CoA pool depletion is not determined
    • Replication in primary human dendritic cells lacking
  9. 2025 Medium

    Identification of LMNA and DLAT as SUCLG2 interaction partners connected SUCLG2 to histone lactylation-mediated transcriptional regulation and nuclear lamin acetylation in glioblastoma, suggesting roles beyond mitochondrial metabolism.

    Evidence Co-immunoprecipitation of SUCLG2 with LMNA and DLAT, acetylation and lactylation assays, ChIP, proliferation and apoptosis readouts in GBM cells

    PMID:41249152

    Open questions at the time
    • SUCLG2-LMNA and SUCLG2-DLAT interactions lack reciprocal pull-down validation and structural characterization
    • Nuclear or cytoplasmic pool of SUCLG2 mediating these interactions is not defined
    • Findings are from a single lab and single cancer type

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the GDP-forming holoenzyme, the mechanism by which SUCLG2 promotes SDH complex II assembly, whether SUCLG2 operates outside mitochondria under physiological conditions, and the clinical penetrance of germline SUCLG2 variants in tumor predisposition.
  • No high-resolution structure of SUCLG1-SUCLG2 heterodimer
  • Mechanism coupling SUCLG2 to SDH assembly unresolved
  • SUCLG2 extra-mitochondrial functions require independent confirmation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-1643685 Disease 2
Partners
DLATLMNASIRT5SUCLG1TRIM21
Complex memberships
Succinyl-CoA ligase (GDP-forming) heterodimer (SUCLG1-SUCLG2)

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SUCLG2 encodes the GTP-specific beta subunit (G-beta) of succinyl-CoA synthetase. The ATP-specific (SUCLA2/A-beta) and GTP-specific (SUCLG2/G-beta) isoforms share the same alpha subunit but differ in their beta subunits, which are only ~53% identical. Both beta subunits were sequenced and confirmed by PCR across multiple mammalian species, establishing that two distinct succinyl-CoA synthetase isoenzymes exist in multicellular eukaryotes. Reverse transcription-PCR, sequence alignment, identification of expressed sequence tags The Journal of biological chemistry High 9765291
2004 SUCLG2 (GDP-forming succinyl-CoA synthetase beta subunit) is expressed in mammalian tissues with tissue-specific variation in relative amounts compared to the ADP-forming isoform (SUCLA2). The GDP-forming enzyme containing SUCLG2 supports GTP-dependent anabolic processes, while the ADP-forming enzyme augments ATP production, and both catalyze the citric acid cycle reaction. Shuttle mechanisms were proposed to explain transfer of high-energy phosphate between the cytosol and mitochondrial matrix. Western blot, Northern blot, enzymatic assays across mammalian tissues The Journal of biological chemistry High 15234968
2011 SUCLG2 knockdown in human fibroblasts (including SUCLA2-deficient patient fibroblasts) caused significant decrease in mitochondrial DNA (mtDNA) content, decreased nucleoside diphosphate kinase (NDPK) activity, decreased cytochrome c oxidase activity, and marked growth impairment. This demonstrates that SUCLG2 is crucial for mtDNA maintenance through its association with mitochondrial NDPK, explaining how SUCL deficiency leads to mtDNA depletion syndrome. shRNA knockdown, mtDNA quantification, NDPK activity assay, cytochrome c oxidase activity assay, cell growth measurement Biochimica et biophysica acta High 21295139
2014 SUCLG2 protein localizes to the mitochondrial network in human fibroblasts (confirmed by co-localization with MitoTracker Orange) and is expressed in cells forming the cerebral microvasculature in human cortical tissue. SUCLG2 is absent from astroglia (GFAP+, S100+), microglia (Iba1+), and oligodendroglia (MBP+), consistent with the absence of matrix substrate-level phosphorylation in glial cells. Double immunofluorescence confocal microscopy, MitoTracker co-localization, in situ hybridization, Western blot Journal of bioenergetics and biomembranes Medium 25370487
2018 Mutation of the alpha subunit SUCLG1 (p.Ala209Glu) causes mislocalization of SUCLG2 protein — SUCLG2 co-localizes only partially with the mitochondrial network rather than fully, and SUCLG2 protein levels are greatly reduced. This is accompanied by impaired mitochondrial substrate-level phosphorylation, increased mitochondrial fragmentation, and mild mtDNA depletion, establishing that proper SUCLG1 is required for correct SUCLG2 mitochondrial localization and succinyl-CoA ligase complex integrity. Confocal immunocytochemistry (triple labeling), oxygen consumption assay, mitochondrial substrate-level phosphorylation measurement, immunoblot, mtDNA quantification Molecular genetics and metabolism High 30470562
2020 In prostate cancer cells, EGFR-LIFR signaling induces SUCLG2 expression downstream of androgen deprivation therapy. Nuclear EGFR acts as a transcriptional regulator binding the LIFR promoter, and LIFR upregulation drives SUCLG2 expression. SUCLG2 upregulation increases succinate synthesis and enhances mitochondrial NDPK enzymatic activity, promoting neuroendocrine differentiation and glycolysis. Knockdown of SUCLG2 suppressed neuroendocrine differentiation in cultured cells and reduced tumor growth in xenograft models. ChIP (EGFR binding to LIFR promoter), SUCLG2 knockdown, NDPK activity assay, xenograft tumor model, immunohistochemistry Oncogene Medium 32963351
2022 Germline variants in the GTP-binding domain of SUCLG2 are found in pheochromocytoma/paraganglioma patients. SUCLG2-deficient tumor cells and hPheo1 cells with SUCLG2 ablation show absence of SUCLG2 protein, decreased SDHB subunit levels, faulty assembly of mitochondrial complex II (succinate dehydrogenase), aberrant respiration, and elevated succinate accumulation, establishing SUCLG2 as required for SDH complex II assembly and function. Genetic panel sequencing, SUCLG2 ablation and re-expression in hPheo1 cells, protein immunoblot (SDHB), respiratory assay, succinate measurement Journal of the National Cancer Institute High 34415331
2023 SUCLG2 controls the overall succinylation landscape in lung adenocarcinoma cells. Deletion of SUCLG2 upregulates succinylation of mitochondrial proteins, inhibiting key metabolic enzymes by reducing enzymatic activity or protein stability, thereby dampening mitochondrial function. SUCLG2 itself is succinylated at Lys93, which enhances its protein stability. SIRT5 desuccinylates SUCLG2 at Lys93, leading to TRIM21-mediated K63-linked ubiquitination and lysosomal degradation of SUCLG2. Succinylome mass spectrometry, SUCLG2 deletion, site-directed mutagenesis (Lys93), enzymatic activity assays, protein stability assays, SIRT5 knockdown/overexpression, Co-IP with TRIM21, ubiquitination assay, lysosome inhibitor treatment Advanced science High 37904651
2023 Suclg2 maintains the tolerogenic phenotype of regulatory dendritic cells (diffDCs) by suppressing NF-κB signaling. Suclg2 inhibits succinylation of Lactb at lysine 288; without Suclg2, Lactb is succinylated and acts as a positive regulator of NF-κB signaling, promoting inflammatory gene expression (CD40, Ccl5, Il12b) and impairing T cell apoptosis induction. Suclg2 siRNA interference, NF-κB signaling assay, succinylation site identification (Lactb K288), metabolomic and transcriptomic profiling, functional immune assays Journal of autoimmunity Medium 37216870
2025 SUCLG2 interacts with LMNA (Lamin A/C), leading to acetylation of LMNA at K470 and affecting oxidative phosphorylation and mitochondrial integrity. SUCLG2 also interacts with DLAT, reducing H4K16la (lactylation) binding to gene promoters and cis-regulatory elements, thereby suppressing expression of BEST1, GRAMD4, and MBD6 and influencing GBM cell proliferation and apoptosis. Co-immunoprecipitation (SUCLG2-LMNA, SUCLG2-DLAT), acetylation and lactylation assays, ChIP, gene expression analysis, SUCLG2 knockdown with proliferation/apoptosis readouts Cell death discovery Medium 41249152

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 1451 20881960
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2014 An atlas of genetic influences on human blood metabolites. Nature genetics 1209 24816252
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Genome-scale RNAi screen for host factors required for HIV replication. Cell host & microbe 627 18976975
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2019 Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality. Cancer cell 298 31056398
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
2015 ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 209 26618866
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2008 Systematic identification of mRNAs recruited to argonaute 2 by specific microRNAs and corresponding changes in transcript abundance. PloS one 148 18461144
2014 Cochaperone binding to LYR motifs confers specificity of iron sulfur cluster delivery. Cell metabolism 133 24606901
1998 Genetic evidence for the expression of ATP- and GTP-specific succinyl-CoA synthetases in multicellular eucaryotes. The Journal of biological chemistry 133 9765291
2010 RioK1, a new interactor of protein arginine methyltransferase 5 (PRMT5), competes with pICln for binding and modulates PRMT5 complex composition and substrate specificity. The Journal of biological chemistry 131 21081503
1999 Ocular albinism: evidence for a defect in an intracellular signal transduction system. Nature genetics 116 10471510
2021 Protein interaction landscapes revealed by advanced in vivo cross-linking-mass spectrometry. Proceedings of the National Academy of Sciences of the United States of America 113 34349018
2004 Expression of two succinyl-CoA synthetases with different nucleotide specificities in mammalian tissues. The Journal of biological chemistry 110 15234968
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2023 SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 66 37904651
2011 The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion. Biochimica et biophysica acta 48 21295139
2020 EGFR-upregulated LIFR promotes SUCLG2-dependent castration resistance and neuroendocrine differentiation of prostate cancer. Oncogene 35 32963351
2023 METTL3-stabilized super enhancers-lncRNA SUCLG2-AS1 mediates the formation of a long-range chromatin loop between enhancers and promoters of SOX2 in metastasis and radiosensitivity of nasopharyngeal carcinoma. Clinical and translational medicine 34 37658588
2022 Germline SUCLG2 Variants in Patients With Pheochromocytoma and Paraganglioma. Journal of the National Cancer Institute 33 34415331
2018 Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder. Molecular genetics and metabolism 25 30470562
2023 Metabolic enzyme Suclg2 maintains tolerogenicity of regulatory dendritic cells diffDCs by suppressing Lactb succinylation. Journal of autoimmunity 16 37216870
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
2024 Regulatory function and mechanism research for m6A modification WTAP via SUCLG2-AS1- miR-17-5p-JAK1 axis in AML. BMC cancer 7 38233760
2025 CircPSD3 aggravates tumor progression by maintaining TCA cycle and mitochondrial function via regulating SUCLG2 in thyroid carcinoma. Cell death & disease 1 40925894
2025 Knockdown of SUCLG2 inhibits glioblastoma proliferation and promotes apoptosis through LMNA acetylation and the mediation of H4K16la lactylation. Cell death discovery 1 41249152