Affinage

SLC25A11

Mitochondrial 2-oxoglutarate/malate carrier protein · UniProt Q02978

Length
314 aa
Mass
34.1 kDa
Annotated
2026-06-10
15 papers in source corpus 11 papers cited in narrative 12 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

SLC25A11 (the mitochondrial 2-oxoglutarate/malate carrier, OGC) is an inner-membrane antiporter that shuttles cytosolic reducing equivalents into mitochondria as the malate-aspartate-shuttle (MAS) antiporter, supporting oxidative ATP production; its loss impairs ATP generation, NADH transport, and oxygen consumption, and suppresses cancer cell growth and KRAS-driven tumorigenesis (PMID:30686754, PMID:40405188). Its transmembrane architecture is built from six alpha-helical segments compatible with a homology model based on the ADP/ATP carrier (PMID:19192628), and the functional protein operates as a dimer whose stability and dimerization are required for activity (PMID:38796028). Beyond bioenergetics, SLC25A11 maintains mitochondrial glutathione (mtGSH) and redox balance, and its depletion drives lipid peroxidation and ferroptosis through ACSL4/LPCAT3/PEBP1 and disrupted NRF2-FSP1 signaling (PMID:38796028, PMID:41514409, PMID:41404734). SLC25A11 also feeds a mitochondrion-to-nucleus alpha-ketoglutarate (alphaKG) supply line acting downstream of GPT2 transaminase to provide nuclear alphaKG for KDM2A-dependent H3K36me2 demethylation and rRNA transcription, a function rescuable by cell-permeable alphaKG (PMID:41227300). The carrier's abundance is post-transcriptionally and post-translationally tuned — OTUD1 deubiquitinates and stabilizes it, METTL3-mediated m6A modification of its 3'UTR (read by YTHDF2) lowers its expression under hypoxia, and NETs destabilize it (PMID:38796028, PMID:40664662, PMID:41404734). Functionally it behaves as a tumor suppressor in chromaffin cells, where germline loss-of-function mutations with loss of heterozygosity produce pseudohypoxic and hypermethylator phenotypes resembling SDHx- and FH-mutant tumors (PMID:29431636). In the C. elegans orthologue MISC-1/OGC, the carrier is required for mitochondrial fusion/fission and cristae integrity and interacts with anti-apoptotic Bcl-xL/CED-9 and pro-apoptotic ANT to govern caspase-dependent apoptosis (PMID:21448454).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2007 Medium

    Established the transmembrane structural framework of OGC/SLC25A11, defining its six-helix mitochondrial-carrier fold before any high-resolution structure existed.

    Evidence NMR and CD spectroscopy of synthetic TMS I-VI peptides with homology modeling against the ADP/ATP carrier

    PMID:19192628

    Open questions at the time
    • No functional mutagenesis to map transport residues
    • Peptides studied in micelles/TFE rather than full-length protein in a membrane
  2. 2011 Medium

    Connected the carrier to mitochondrial dynamics and apoptosis, showing the orthologue is needed for fusion/fission and physically couples to apoptotic regulators.

    Evidence Reciprocal pull-downs, TEM, RNAi, genetic epistasis and caspase assays in C. elegans (MISC-1) with mammalian OGC

    PMID:21448454

    Open questions at the time
    • Bcl-xL/ANT interactions not validated structurally or in mammalian cells
    • Mechanism linking transport activity to cristae morphology unresolved
  3. 2018 Medium

    Defined SLC25A11 as a tumor suppressor whose loss phenocopies metabolic-driven tumor syndromes, framing the carrier within epigenetic/metabolic tumorigenesis.

    Evidence Whole-exome sequencing, LOH analysis, and CRISPR-Cas9 knockout with metabolic/epigenetic phenotyping in mouse chromaffin cells

    PMID:29431636

    Open questions at the time
    • Direct metabolite mechanism producing the hypermethylator phenotype not pinned to a single pathway
    • Single tumor-cell context
  4. 2019 Medium

    Demonstrated the carrier's bioenergetic role as the MAS antiporter and its requirement for cancer growth in vivo, establishing functional importance beyond a housekeeping transporter.

    Evidence siRNA knockdown with ATP/NADH and metabolite profiling in NSCLC/melanoma, plus heterozygous Slc25a11 KO crossed into a KRAS lung tumor model

    PMID:30686754

    Open questions at the time
    • Reconciliation with the earlier tumor-suppressor finding (context-dependence) not resolved
    • Knockdown rather than catalytic-dead rescue
  5. 2024 Medium

    Linked carrier dimer stability to mitochondrial glutathione homeostasis and ferroptosis, identifying a redox-protective function destabilized by extracellular NETs.

    Evidence Blue native PAGE dimerization analysis, NET treatment of SMCs, Padi4 KO mice, and ferroptosis modulator experiments in an angiotensin II AAA model

    PMID:38796028

    Open questions at the time
    • Molecular event by which NETs reduce dimerization unknown
    • Whether mtGSH transport is direct or indirect not established
  6. 2025 Medium

    Established post-translational and post-transcriptional control of SLC25A11 abundance via OTUD1 deubiquitination and METTL3/YTHDF2 m6A regulation, explaining context-dependent levels under stress.

    Evidence Deubiquitination and Co-IP assays (OTUD1, NPC radiosensitivity); m6A methylation/RIP assays with OE/KD epistasis and STM2457 in hypoxic cardiomyocytes

    PMID:40664662 PMID:41404734

    Open questions at the time
    • Ubiquitin ligase that opposes OTUD1 not identified
    • Whether OTUD1 and m6A pathways co-regulate the carrier in the same tissue untested
  7. 2025 Medium

    Generalized SLC25A11 loss-driven ferroptosis to multiple disease contexts and tied it to NRF2-FSP1 and EMP/EMT signaling, broadening the carrier's role in redox and cell-state control.

    Evidence KD/OE with lipid-ROS, NRF2 localization, NRF2-FSP1 interaction, ferrostatin-1 rescue in biliary tract cancer; KD/OE with pSmad2/3 PI3K/AKT readouts and OGC+/- mice in RPE fibrosis

    PMID:41147690 PMID:41514409

    Open questions at the time
    • Mechanistic link from transport activity to NRF2 regulation not defined
    • Cell-type specificity of the EMT effect unresolved
  8. 2025 Medium

    Placed SLC25A11 in a defined mitochondrion-to-nucleus alphaKG relay (GPT2 -> SLC25A11) required for KDM2A-dependent histone demethylation and rRNA transcription, providing a direct metabolic-epigenetic mechanism.

    Evidence alphaKG biosensor genetic screen, siRNA KD, N-phenylmaleimide inhibition, ChIP for H3K36me2, rRNA assays, and dimethyl-alphaKG rescue in MCF-7 cells; GPT2-deficient mouse model

    PMID:41227300

    Open questions at the time
    • Preprint component (GPT2->SLC25A11 ordering) not yet peer-reviewed
    • How nuclear alphaKG is delivered from the matrix carrier output not mechanistically traced
  9. 2025 Medium

    Validated SLC25A11 as a druggable MAS antiporter, with pharmacological inhibition reducing tumor bioenergetics, stemness, and growth.

    Evidence N-phenylmaleimide (KN612) inhibition corroborated by siRNA KD, OCR/ATP assays, and orthotopic glioblastoma xenografts

    PMID:40405188

    Open questions at the time
    • Target selectivity of N-phenylmaleimide compounds for SLC25A11 not fully characterized
    • Therapeutic window versus normal MAS function untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how SLC25A11 reconciles its opposing roles as a growth-supporting bioenergetic carrier and a tumor-suppressor/ferroptosis-protective factor across tissues.
  • No structural model of the transport cycle with bound substrates
  • No unified explanation for context-dependent pro- versus anti-tumor behavior
  • Direct demonstration of mtGSH transport by the purified carrier lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140104 molecular carrier activity 3
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-1430728 Metabolism 3 R-HSA-4839726 Chromatin organization 2
Partners
ANTBCL-XLFSP1NRF2OTUD1YTHDF2

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 Germline loss-of-function mutations in SLC25A11 (encoding the mitochondrial 2-oxoglutarate/malate carrier) act as a tumor-suppressor mechanism: mutations were associated with loss of heterozygosity, and CRISPR-Cas9 knockout of Slc25a11 in mouse chromaffin cells recapitulated pseudohypoxic and hypermethylator phenotypes comparable to SDHx- and FH-mutant tumors. Whole-exome sequencing, CRISPR-Cas9 knockout, loss-of-heterozygosity analysis, metabolic/epigenetic phenotyping of KO cells Cancer research Medium 29431636
2019 SLC25A11 functions as the oxoglutarate carrier mediating transport of cytosolic NADH (as malate) into the mitochondria via the malate-aspartate shuttle; SLC25A11 knockdown in NSCLC and melanoma cells significantly impaired ATP production and inhibited cancer cell growth, and heterozygous Slc25a11 knockout mice showed suppressed KRAS-driven lung tumor formation. siRNA knockdown, ATP/NADH measurement, metabolite profiling, in vivo cross-breeding with KRASLA2 mouse model EBioMedicine Medium 30686754
2011 MISC-1/OGC (C. elegans orthologue of mammalian OGC/SLC25A11) is required for mitochondrial fusion and fission; its loss results in decreased mitochondrial cristae with blebbed appearance. Pull-down experiments show MISC-1 and OGC interact with anti-apoptotic proteins CED-9 and Bcl-xL, respectively, and with pro-apoptotic protein ANT. Knockdown induces apoptosis via caspase cascade, and genetic analysis places MISC-1 in the apoptotic pathway mediated by LIN-35/Rb-like protein. Pull-down assay (Co-IP), transmission electron microscopy, RNAi knockdown, genetic epistasis, caspase assay PloS one Medium 21448454
2007 NMR and CD spectroscopy of synthetic peptides corresponding to all six transmembrane segments (TMS I–VI) of OGC/SLC25A11 in TFE/water and SDS micelles revealed alpha-helical structures; structural data were found compatible with a homology model based on the ATP/ADP carrier X-ray structure, providing structural characterization of the transmembrane architecture. NMR spectroscopy, CD spectroscopy, homology modeling using synthetic transmembrane segment peptides The Italian journal of biochemistry Medium 19192628
2024 Neutrophil extracellular traps (NETs) decrease the stability and dimerization of SLC25A11 (assessed by blue native PAGE), leading to depletion of mitochondrial glutathione (mitoGSH) and subsequent ferroptosis in smooth muscle cells; this mechanism promotes abdominal aortic aneurysm formation in an angiotensin II mouse model. Blue native PAGE (dimerization analysis), Western blot, immunofluorescence, in vitro NET treatment of SMCs, Padi4 knockout mouse model, ferroptosis inhibitor/activator experiments, TEM Free radical biology & medicine Medium 38796028
2025 OTUD1 deubiquitinase stabilizes SLC25A11 by deubiquitinating it; OTUD1-mediated stabilization of SLC25A11 increases ROS and apoptosis, thereby enhancing radiosensitivity of nasopharyngeal carcinoma cells. The upstream regulator TFAP2C controls OTUD1 expression via methylation. Deubiquitination assay, co-immunoprecipitation, siRNA knockdown, overexpression, in vitro and in vivo radiosensitivity assays Cell death & disease Medium 40664662
2025 Pharmacological inhibition of SLC25A11 by N-phenylmaleimide (KN612) in glioblastoma tumorspheres decreases oxygen consumption rate, ATP levels, mitochondrial activity, stemness, and invasion; siRNA-mediated SLC25A11 knockdown recapitulates these effects, confirming SLC25A11 as the MAS antiporter target. KN612 also reduced tumor size and prolonged survival in an orthotopic xenograft model. siRNA knockdown, pharmacological inhibition (KN612), oxygen consumption rate measurement, ATP assay, transcriptome analysis, in vivo orthotopic xenograft Cancer cell international Medium 40405188
2025 OGC/SLC25A11 silencing in RPE cells aggravates TGF-β2-induced epithelial-to-mesenchymal transition (EMT), reduces mitochondrial respiration and mtGSH, and activates pSmad2/3 via PI3K/AKT signaling; overexpression of OGC attenuates EMT. In vivo, OGC+/- mice showed augmented subretinal fibrosis via TGF-β2-dependent PI3K signaling. siRNA knockdown and overexpression in ARPE-19 cells, TGF-β2 treatment, mitochondrial bioenergetics assay, OCT and immunostaining in OGC+/- mice, signaling pathway inhibitors Aging cell Medium 41147690
2025 SLC25A11 inhibition (by N-phenylmaleimide or siRNA knockdown) reduces NRF2 expression and its nuclear translocation, disrupts NRF2-FSP1 interaction, activates ACSL4/LPCAT3/PEBP1-dependent lipid peroxidation, and induces ferroptosis in biliary tract cancer; ferrostatin-1 rescues this phenotype by reducing lipid peroxidation. SLC25A11 knockdown and overexpression, RNA sequencing, lipid ROS measurement, mitochondrial membrane potential assay, NRF2 localization imaging, in vivo animal models Cellular & molecular biology letters Medium 41514409
2025 SLC25A11 (αKG/malate carrier) supplies nuclear α-ketoglutarate downstream of GPT2 transaminase activity; genetic screen and biosensor experiments placed SLC25A11 in a sequential mitochondrial pathway (GPT2 → SLC25A11) that controls nuclear αKG availability for chromatin demethylation. SLC25A11 knockdown blocked AOA-induced KDM2A-dependent reduction in H3K36me2 and rRNA transcription, and this was rescued by cell-permeable αKG. Genetic screen with αKG biosensor, SLC25A11 knockdown (siRNA), N-phenylmaleimide inhibition, dimethyl αKG rescue, H3K36me2 chromatin assay, rRNA transcription measurement, GPT2-deficient mouse model bioRxivpreprint Medium
2025 METTL3-mediated m6A modification of SLC25A11 3'UTR decreases SLC25A11 expression under chronic hypoxia; YTHDF2 binds the modified SLC25A11 3'UTR. SLC25A11 overexpression inhibits chronic hypoxia-induced ferroptosis and mitochondrial dysfunction in cardiomyocytes; SLC25A11 knockdown-induced ferroptosis is reversed by iron chelator deferoxamine. METTL3 inhibitor STM2457 restores SLC25A11 expression and reduces ferroptosis, which is abolished by SLC25A11 knockdown. m6A methylation assay, YTHDF2 RNA pulldown/RIP, SLC25A11 overexpression and shRNA knockdown, cell viability assay, mitochondrial function assay, deferoxamine rescue, STM2457 pharmacological inhibition, hypoxia mouse model Journal of the American Heart Association Medium 41404734
2025 SLC25A11 inhibition (NPM) or knockdown prevents AOA-induced KDM2A activation and H3K36me2 demethylation in the rRNA gene promoter, reducing rRNA transcription; cell-permeable αKG rescues KDM2A activity blocked by SLC25A11 inhibition, demonstrating that SLC25A11-mediated αKG transport is specifically required for KDM2A-dependent epigenetic regulation. N-phenylmaleimide inhibition, siRNA SLC25A11 knockdown, chromatin immunoprecipitation (H3K36me2), rRNA transcription assay, dimethyl αKG rescue in MCF-7 cells Cells Medium 41227300

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas. Cancer research 110 29431636
2019 Loss of SLC25A11 causes suppression of NSCLC and melanoma tumor formation. EBioMedicine 45 30686754
2011 MISC-1/OGC links mitochondrial metabolism, apoptosis and insulin secretion. PloS one 27 21448454
2024 Neutrophil extracellular trap-induced ferroptosis promotes abdominal aortic aneurysm formation via SLC25A11-mediated depletion of mitochondrial glutathione. Free radical biology & medicine 25 38796028
2025 N-phenylmaleimide induces bioenergetic switch and suppresses tumor growth in glioblastoma tumorspheres by inhibiting SLC25A11. Cancer cell international 4 40405188
2025 Combining decitabine with radiotherapy to enhance nasopharyngeal carcinoma radiosensitivity via the TFAP2C-OTUD1-SLC25A11 axis. Cell death & disease 4 40664662
2025 SLC25A11, a Novel Gene Associated With Carney-Stratakis Syndrome. Journal of the Endocrine Society 3 40242210
2014 Bioactive attributes of tomatoes possessing dg, ogc, and rin genes. Food & function 3 24589691
2023 Proteomic analysis by 4D label-free MS-PRM identified that Nptx1, Ptpmt1, Slc25a11, and Cpt1c are involved in diabetes-associated cognitive dysfunction. The International journal of neuroscience 2 38099467
2007 Structural characterization of the transmembrane segments of the mitochondrial oxoglutarate carrier (OGC) by NMR spectroscopy. The Italian journal of biochemistry 2 19192628
2022 Establishment and characterization of IPS-OGC-C1: a novel induced pluripotent stem cell line from healthy human ovarian granulosa cells. Human cell 1 35876985
2026 SLC25A11-mediated reprogramming of mitochondrial redox state and lipid peroxidation confers NRF2-dependent ferroptosis resistance in biliary tract cancer. Cellular & molecular biology letters 0 41514409
2025 Deficiency of 2-Oxoglutarate Carrier (Slc25a11) Drives RPE Epithelial-to-Mesenchymal Transition and Exacerbates Subretinal Fibrosis in Neovascular Age-Related Macular Degeneration. Aging cell 0 41147690
2025 SLC25A11 Is Associated with KDM2A-Dependent Reduction in rRNA Transcription Induced by Aminooxyacetic Acid. Cells 0 41227300
2025 METTL3-m6A-SLC25A11 Axis Promotes Chronic Hypoxia-Induced Cardiomyocyte Ferroptosis. Journal of the American Heart Association 0 41404734

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