Affinage

SUCLG2

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

Length
432 aa
Mass
46.5 kDa
Annotated
2026-06-10
12 papers in source corpus 9 papers cited in narrative 9 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

SUCLG2 is the GTP-forming beta subunit of mitochondrial succinyl-CoA ligase, whose proper localization and stability depend on heterodimerization with the alpha subunit SUCLG1; loss of SUCLG1 mislocalizes SUCLG2 and reduces its protein level, fragmenting mitochondria and impairing substrate-level phosphorylation (PMID:30470562). SUCLG2 resides in the mitochondrial network and, in human cerebral cortex, is selectively expressed in microvascular cells rather than neuronal or glial populations (PMID:25370487). Functionally, SUCLG2 is required for mitochondrial DNA maintenance, an activity linked to its support of mitochondrial nucleoside diphosphate kinase (NDPK) and cytochrome c oxidase activity (PMID:21295139). Beyond its core metabolic role, SUCLG2 governs the global succinylation state of mitochondrial proteins, and its loss raises succinylation of metabolic enzymes to dampen mitochondrial function; SUCLG2 is itself succinylated at Lys93, which stabilizes it, while SIRT5 desuccinylates Lys93 to license TRIM21-mediated K63-ubiquitination and lysosomal degradation (PMID:37904651). Germline variants in the GTP-binding domain abolish SUCLG2 protein, destabilize the SDHB subunit, prevent assembly of complex II (succinate dehydrogenase), and cause succinate accumulation in pheochromocytoma/paraganglioma (PMID:34415331). In cancer, SUCLG2 acquires non-canonical roles: upon EGF stimulation it translocates to the nucleus, complexes with phosphorylated EGFR, co-occupies the VEGFA promoter to drive VEGFA transcription and neuroendocrine differentiation, and confers EGFR-TKI (erlotinib) resistance (PMID:42252434), with EGFR–LIFR signaling upstream upregulating its expression to promote neuroendocrine differentiation and glycolysis (PMID:32963351). SUCLG2 also restrains succinylation-dependent NF-κB signaling in tolerogenic dendritic cells by suppressing Lactb succinylation at Lys288 (PMID:37216870).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2011 High

    Established that SUCLG2 is not merely a TCA-cycle enzyme subunit but is required for mitochondrial DNA maintenance, framing it as a determinant of mitochondrial genome integrity.

    Evidence shRNA knockdown in patient and control fibroblasts with mtDNA quantification, NDPK and cytochrome c oxidase activity assays

    PMID:21295139

    Open questions at the time
    • Mechanistic link between SUCLG2 and NDPK is correlative, not direct
    • Does not resolve whether mtDNA loss is a primary or secondary consequence
  2. 2014 Medium

    Pinned down where SUCLG2 acts in tissue, showing cell-type-specific mitochondrial localization to brain microvasculature rather than ubiquitous expression.

    Evidence Double immunofluorescence with cell-type markers and mitotracker in human cortical tissue and fibroblasts

    PMID:25370487

    Open questions at the time
    • Single tissue type examined
    • Functional significance of microvascular restriction not addressed
  3. 2018 Medium

    Demonstrated that SUCLG2 localization and stability are dependent on its heterodimeric partner SUCLG1, defining the structural basis of the functional enzyme.

    Evidence Patient fibroblasts with SUCLG1 mutations; immunoblotting, confocal co-localization, OCR and enzyme activity assays

    PMID:30470562

    Open questions at the time
    • Indirect (driven by SUCLG1 mutation, not SUCLG2 manipulation)
    • Single lab, patient-derived material
  4. 2020 Medium

    Linked SUCLG2 to oncogenic signaling, showing EGFR-LIFR signaling drives its expression and that elevated SUCLG2 promotes neuroendocrine differentiation and glycolysis in prostate cancer.

    Evidence ChIP, shRNA knockdown, NDPK activity assay, xenograft model, patient IHC

    PMID:32963351

    Open questions at the time
    • Mechanism by which SUCLG2 promotes differentiation not resolved at this stage
    • Single lab
  5. 2022 High

    Identified SUCLG2 as a tumor-relevant gene whose GTP-binding domain variants abolish protein and disrupt SDH complex II assembly, causing succinate accumulation in pheochromocytoma/paraganglioma.

    Evidence Panel sequencing, tumor immunoblotting, hPheo1 ablation and re-expression rescue, succinate measurement, SDH assembly and respiration assays

    PMID:34415331

    Open questions at the time
    • Molecular basis of SUCLG2-dependent SDHB destabilization not defined
    • Disease causality strengthened by rescue but penetrance not addressed
  6. 2023 High

    Defined SUCLG2 as a master regulator of mitochondrial protein succinylation and elucidated a PTM-driven degradation circuit controlling its abundance.

    Evidence Succinylome MS, Lys93 site-directed mutagenesis, Co-IP, enzyme assays, in vitro ubiquitination in lung adenocarcinoma cells

    PMID:37904651

    Open questions at the time
    • Identity of the succinyltransferase opposing SIRT5 not established
    • Direct enzymatic mechanism of succinylation control vs substrate sequestration unresolved
  7. 2023 Medium

    Extended SUCLG2's succinylation-suppressing role to immune regulation, showing it maintains tolerogenic dendritic cells by limiting Lactb K288 succinylation and NF-κB activation.

    Evidence shRNA knockdown in diffDCs, metabolomics, transcriptomics, NF-κB reporter, succinylation site MS, T cell apoptosis assay

    PMID:37216870

    Open questions at the time
    • Causality of Lactb K288 succinylation not validated by mutagenesis
    • Single lab
  8. 2025 Medium

    Reported additional non-metabolic protein interactions of SUCLG2 in glioblastoma affecting LMNA acetylation, OXPHOS, and lactylation-dependent gene expression via DLAT.

    Evidence Co-IP (SUCLG2-LMNA, SUCLG2-DLAT), LMNA K470 acetylation site ID, H4K16la ChIP, OXPHOS and gene expression assays

    PMID:41249152

    Open questions at the time
    • No mutagenesis validation of K470 acetylation site
    • Single study, single lab
  9. 2026 High

    Resolved a non-canonical nuclear function showing SUCLG2 translocates upon EGF stimulation to co-activate VEGFA transcription with phospho-EGFR and drive TKI resistance.

    Evidence Nuclear fractionation, Co-IP with phospho-EGFR, ChIP at VEGFA promoter, erlotinib resistance and rescue assays, xenograft and NEPC organoids

    PMID:42252434

    Open questions at the time
    • Mechanism triggering nuclear import not defined
    • Relationship between nuclear and mitochondrial SUCLG2 pools unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SUCLG2's canonical succinyl-CoA ligase activity is mechanistically coupled to its diverse moonlighting roles (mtDNA maintenance, global succinylation control, nuclear transcriptional co-activation) remains unresolved.
  • No structural model linking GTP-binding domain to non-metabolic functions
  • Regulators of nuclear translocation unknown
  • Enzyme opposing SIRT5 in Lys93 succinylation unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005739 mitochondrion 3 GO:0005634 nucleus 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-392499 Metabolism of proteins 1
Partners
DLATEGFRLMNASIRT5SUCLG1TRIM21
Complex memberships
mitochondrial complex II / succinate dehydrogenase (assembly dependency)succinyl-CoA ligase (SUCLG1-SUCLG2 heterodimer)

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 SUCLG2 controls overall succinylation levels of mitochondrial proteins in lung adenocarcinoma cells; its deletion upregulates succinylation of mitochondrial proteins, reducing enzymatic activity or protein stability of key metabolic enzymes and dampening mitochondrial function. SUCLG2 itself is succinylated on Lys93, which enhances its protein stability. SIRT5 desuccinylates SUCLG2 on Lys93, and TRIM21 then ubiquitinates SUCLG2 via K63-linkage leading to lysosomal degradation. Succinylome mass-spectrometry analysis, site-directed mutagenesis (Lys93), Co-IP, enzyme activity assays, shRNA knockdown, overexpression, in vitro ubiquitination assay Advanced science High 37904651
2011 SUCLG2 knockdown in human fibroblasts (patient and control) caused significant decrease in mitochondrial DNA (mtDNA) content, decreased mitochondrial nucleoside diphosphate kinase (NDPK) and cytochrome c oxidase activities, and marked growth impairment, establishing SUCLG2 as crucial for mtDNA maintenance. The association with mitochondrial NDPK activity suggests SUCLG2 supports mtDNA maintenance via NDPK. shRNA knockdown of SUCLG2 in patient-derived and control fibroblasts; measurement of mtDNA content (quantitative PCR), NDPK activity assay, cytochrome c oxidase activity assay, cell growth assay Biochimica et biophysica acta High 21295139
2020 EGFR-LIFR signaling upregulates SUCLG2 expression in prostate cancer cells; nuclear EGFR acts as a transcriptional regulator by directly binding the LIFR promoter. SUCLG2 upregulation increases succinate synthesis and enzymatic activities of mitochondrial NDPK, and promotes neuroendocrine differentiation and glycolysis in prostate cancer. Knockdown of SUCLG2 suppressed neuroendocrine differentiation in vitro and reduced xenograft tumor growth. ChIP (EGFR binding to LIFR promoter), shRNA knockdown of SUCLG2, NDPK activity assay, xenograft tumor model, immunohistochemistry of patient tissue Oncogene Medium 32963351
2022 Germline variants in the GTP-binding domain of SUCLG2 cause absence of SUCLG2 protein, decrease in SDHB subunit levels, faulty assembly of mitochondrial complex II (succinate dehydrogenase), aberrant mitochondrial respiration, and elevated succinate accumulation in pheochromocytoma/paraganglioma tumors and SUCLG2-deficient hPheo1 cells. Genetic panel sequencing, immunoblotting of tumor samples, SUCLG2 ablation and re-expression in hPheo1 cell line, succinate measurement, SDH complex assembly assay, respiration assay Journal of the National Cancer Institute High 34415331
2018 Mutations in SUCLG1 (the alpha subunit) lead to strongly reduced SUCLG1 protein, which causes mislocalization of SUCLG2 protein (partial co-localization with mitochondrial network by confocal imaging), morphological fragmentation of mitochondria, impaired mitochondrial substrate-level phosphorylation (mSLP), and reduction of SUCLA2 and SUCLG2 protein levels. This establishes that SUCLG2 localization and stability depend on its heterodimeric partner SUCLG1. Immunoblotting, confocal triple immunocytochemistry with mitotracker, oxygen consumption rate assay, in situ enzyme activity assay, mtDNA quantification in patient skin fibroblasts Molecular genetics and metabolism Medium 30470562
2014 In human cerebral cortex, SUCLG2 protein is localized to cells forming the microvasculature (not neurons, astroglia, microglia, or oligodendroglia), as determined by double immunofluorescence. Co-localization with mitotracker in fibroblasts confirmed SUCLG2 resides in the mitochondrial network. This establishes cell-type-specific mitochondrial localization of SUCLG2 in the brain. Double immunofluorescence (SUCLG2 with Iba1, myelin basic protein, GFAP, S100, mitotracker orange) in human cortical tissue and fibroblast cultures, Western blotting Journal of bioenergetics and biomembranes Medium 25370487
2023 Suclg2 maintains the tolerogenic phenotype of regulatory dendritic cells (diffDCs) by suppressing succinylation of Lactb at lysine 288. In diffDCs, Suclg2 prevents NF-κB signaling activation; Suclg2 knockdown enhanced NF-κB signaling and expression of inflammatory genes (CD40, Ccl5, Il12b) and impaired T cell apoptosis induction. Lactb succinylation at K288 was identified as a positive regulator of NF-κB signaling that Suclg2 suppresses. Suclg2 shRNA knockdown in diffDCs, metabolomics, transcriptomics, NF-κB reporter assay, succinylation site identification (mass spectrometry), functional T cell apoptosis assay, inflammatory gene expression Journal of autoimmunity Medium 37216870
2026 EGF stimulation induces SUCLG2 nuclear translocation in prostate cancer cells, where SUCLG2 forms a complex with phosphorylated EGFR and co-occupies the VEGFA promoter to co-activate VEGFA transcription, driving neuroendocrine gene programs. SUCLG2 overexpression conferred erlotinib (EGFR-TKI) resistance in vitro, and SUCLG2 depletion restored TKI sensitivity; VEGFA reconstitution rescued the effect of SUCLG2 depletion. Nuclear fractionation/immunofluorescence for SUCLG2 translocation, Co-IP of SUCLG2 with phospho-EGFR, ChIP of SUCLG2 and EGFR at VEGFA promoter, SUCLG2 overexpression/depletion with erlotinib resistance assay, xenograft model, patient-derived NEPC organoids Cell communication and signaling High 42252434
2025 SUCLG2 interacts with LMNA in glioblastoma cells, leading to acetylation of LMNA at K470, which affects oxidative phosphorylation levels and mitochondrial damage. SUCLG2 also interacts with DLAT, reducing binding of H4K16la (lactylation mark) to promoter regions, thereby suppressing expression of BEST1, GRAMD4, and MBD6 and affecting GBM cell proliferation and apoptosis. Co-immunoprecipitation (SUCLG2-LMNA and SUCLG2-DLAT), acetylation site identification (K470 on LMNA), H4K16la ChIP, gene expression analysis after SUCLG2 knockdown, OXPHOS and mitochondrial damage assays Cell death discovery Medium 41249152

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2023 SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 69 37904651
2011 The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion. Biochimica et biophysica acta 48 21295139
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 35 37658588
2020 EGFR-upregulated LIFR promotes SUCLG2-dependent castration resistance and neuroendocrine differentiation of prostate cancer. Oncogene 35 32963351
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 17 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 8 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
2026 Co-targeting EGFR and SUCLG2 disrupts a nuclear transcriptional program driving neuroendocrine differentiation and TKI resistance in castration-resistant prostate cancer. Cell communication and signaling : CCS 0 42252434

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