Affinage

SLC25A11

Mitochondrial 2-oxoglutarate/malate carrier protein · UniProt Q02978

Round 2 corrected
Length
314 aa
Mass
34.1 kDa
Annotated
2026-04-28
45 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC25A11 is the inner mitochondrial membrane 2-oxoglutarate/malate antiporter that operates as a core component of the malate-aspartate shuttle, transferring cytosolic NADH equivalents into mitochondria to sustain oxidative phosphorylation and ATP production (PMID:30686754, PMID:40405188). Beyond this canonical bioenergetic role, SLC25A11 transports glutathione into the mitochondrial matrix, and disruption of its dimerization depletes mitochondrial GSH and triggers ferroptosis (PMID:38796028, PMID:41514409, PMID:41404734). SLC25A11-mediated export of α-ketoglutarate from mitochondria supplies the cofactor required for KDM2A-dependent histone demethylation, linking mitochondrial metabolite exchange to epigenetic regulation, and germline loss-of-function mutations in SLC25A11 cause pseudohypoxic/hypermethylator phenotypes that predispose to metastatic paraganglioma (PMID:41227300, PMID:29431636). Protein stability of SLC25A11 is controlled by OTUD1-mediated deubiquitination, while its mRNA abundance is regulated by METTL3/YTHDF2-dependent m6A modification (PMID:40664662, PMID:41404734).

Mechanistic history

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

    Determining whether the OGC adopts the predicted six-transmembrane-helix architecture was essential for placing it within the mitochondrial carrier family; CD/NMR spectroscopy of all six transmembrane segments confirmed α-helical structures consistent with the ADP/ATP carrier fold.

    Evidence CD and NMR spectroscopy of synthetic OGC transmembrane peptides with homology modeling

    PMID:19192628

    Open questions at the time
    • No full-length structure determined
    • No mutagenesis to test functional residues
    • Peptide fragments studied in detergent/TFE rather than a lipid bilayer
  2. 2011 High

    Whether SLC25A11 participates in processes beyond metabolite transport was unclear; interaction with anti-apoptotic CED-9/Bcl-xL and pro-apoptotic ANT, and genetic epistasis with the LIN-35/Rb pathway, established a role for OGC in mitochondrial morphology control and apoptosis induction.

    Evidence Pull-down assays, RNAi knockdown with apoptosis scoring, TEM, genetic epistasis in C. elegans and mammalian cells

    PMID:21448454

    Open questions at the time
    • Whether the apoptotic role is conserved in all mammalian tissues remains unresolved
    • No direct measurement of transport activity during apoptosis
  3. 2018 High

    The question of whether SLC25A11 loss could be oncogenic was answered when germline loss-of-function mutations were found in paraganglioma patients and CRISPR knockout reproduced pseudohypoxic and hypermethylator phenotypes, establishing SLC25A11 as a tumor suppressor gene analogous to SDHx/FH.

    Evidence Whole-exome sequencing of seven patients, LOH analysis, CRISPR-Cas9 knockout in mouse chromaffin cells with metabolic/epigenetic profiling

    PMID:29431636

    Open questions at the time
    • No rescue experiment restoring SLC25A11 in knockout cells
    • Penetrance and spectrum of associated tumors not fully defined
  4. 2019 High

    How SLC25A11 supports tumor bioenergetics was clarified by showing that cancer cells rely on its malate-aspartate shuttle activity for mitochondrial NADH import and ATP production; knockdown impaired ATP synthesis, and heterozygous Slc25a11 knockout suppressed KRAS-driven lung tumorigenesis in vivo.

    Evidence siRNA knockdown with ATP/NADH measurement in NSCLC/melanoma lines, heterozygous Slc25a11 knockout crossed with KRAS-driven lung tumor model

    PMID:30686754

    Open questions at the time
    • Whether other shuttle components compensate at different stoichiometries is unknown
    • No direct flux measurement of malate/oxoglutarate exchange rates
  5. 2024 High

    Whether SLC25A11 directly controls mitochondrial glutathione was uncertain; demonstration that NETs destabilize SLC25A11 dimers, deplete mitoGSH, and induce ferroptosis in smooth muscle cells established a non-canonical transport function—mitochondrial glutathione import—governed by SLC25A11 oligomeric state.

    Evidence Blue native PAGE (dimerization), mitoGSH quantification, ferroptosis assays in SMCs, angiotensin II AAA mouse model with PAD4 KO

    PMID:38796028

    Open questions at the time
    • Direct reconstitution of GSH transport by purified SLC25A11 not yet performed
    • Structural basis of how dimerization controls GSH versus α-KG transport is unknown
  6. 2025 Medium

    Multiple 2025 studies converged on ferroptosis as a downstream consequence of SLC25A11 loss: m6A-mediated mRNA degradation by METTL3/YTHDF2 reduces SLC25A11 in hypoxic cardiomyocytes causing ferroptosis, and SLC25A11 depletion in biliary tract cancer activates ACSL4/LPCAT3/PEBP1 lipid peroxidation via NRF2-FSP1 axis collapse, consolidating ferroptosis as a central phenotype of SLC25A11 deficiency.

    Evidence MeRIP and RIP for m6A/YTHDF2-SLC25A11 mRNA interaction with genetic rescue in cardiomyocytes; NRF2-FSP1 Co-IP and ferrostatin-1 rescue in biliary tract cancer cells; in vivo models

    PMID:41404734 PMID:41514409

    Open questions at the time
    • Whether m6A regulation of SLC25A11 occurs in non-cardiac tissues is untested
    • Relative contribution of GSH depletion versus α-KG imbalance to ferroptosis not dissected
  7. 2025 Medium

    How SLC25A11 protein levels are maintained was answered by showing OTUD1 deubiquitinates SLC25A11, stabilizing it; loss of this axis increases radioresistance in nasopharyngeal carcinoma through reduced mitochondrial ROS and apoptosis.

    Evidence Co-IP and deubiquitination assay for OTUD1-SLC25A11, siRNA/overexpression with ROS and apoptosis readouts, in vivo radioresistance model

    PMID:40664662

    Open questions at the time
    • Ubiquitination sites on SLC25A11 not mapped
    • E3 ligase responsible for SLC25A11 ubiquitination not identified
  8. 2025 Medium

    The question of whether SLC25A11-exported α-ketoglutarate feeds nuclear epigenetic reactions was answered: SLC25A11 inhibition blocks α-KG-dependent KDM2A demethylation of H3K36me2 at rRNA gene promoters, and cell-permeable α-KG rescues the defect, establishing a mitochondria-to-nucleus metabolite signaling axis.

    Evidence N-phenylmaleimide inhibition and siRNA knockdown of SLC25A11, H3K36me2 ChIP at rRNA promoter, dimethyl-α-KG rescue in MCF-7 cells

    PMID:41227300

    Open questions at the time
    • Whether this axis extends to other α-KG-dependent demethylases (e.g., TET enzymes) via SLC25A11 is untested
    • Direct measurement of nuclear α-KG pools not performed
  9. 2025 Medium

    SLC25A11 haploinsufficiency aggravates EMT and subretinal fibrosis via PI3K/AKT/Smad2/3 signaling, extending the carrier's pathological relevance beyond cancer to fibrotic eye disease.

    Evidence siRNA/overexpression in RPE cells, EMT markers and pathway analysis, OGC+/− mice with laser-induced subretinal fibrosis

    PMID:41147690

    Open questions at the time
    • Whether mitoGSH depletion or α-KG imbalance drives the EMT phenotype is not resolved
    • Single tissue context (RPE cells)

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of SLC25A11 in a lipid membrane, direct reconstitution of GSH transport, identification of the E3 ubiquitin ligase counterpart to OTUD1, and whether the distinct transport cargoes (malate/α-KG versus GSH) use shared or distinct conformational mechanisms.
  • No high-resolution cryo-EM or crystal structure of SLC25A11
  • No reconstituted proteoliposome assay distinguishing GSH from α-KG transport
  • E3 ligase targeting SLC25A11 for ubiquitination unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140104 molecular carrier activity 2
Localization
GO:0005739 mitochondrion 7
Pathway
R-HSA-5357801 Programmed Cell Death 5 R-HSA-1643685 Disease 4 R-HSA-382551 Transport of small molecules 4 R-HSA-1430728 Metabolism 3 R-HSA-4839726 Chromatin organization 2
Partners
ANTBCL2L1GPT2OTUD1YTHDF2

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 The C. elegans ortholog MISC-1 (and mammalian OGC/SLC25A11) controls mitochondrial morphology (fusion and fission) and participates in apoptosis induction through interaction with anti-apoptotic proteins CED-9/Bcl-xL and pro-apoptotic ANT, as demonstrated by pull-down experiments; knockdown of misc-1/OGC induces apoptosis via the caspase cascade, and MISC-1 controls apoptosis through the LIN-35/Rb-like protein pathway. Pull-down assays (MISC-1/OGC interaction with CED-9, Bcl-xL, ANT), genetic epistasis (LIN-35/Rb pathway), RNAi knockdown with apoptosis readout, transmission electron microscopy (mitochondrial cristae morphology) PloS one High 21448454
2007 Structural characterization of all six transmembrane segments (TMS I–VI) of OGC/SLC25A11 by CD and NMR spectroscopy revealed alpha-helical structures in TFE/water and SDS micelles; the helical structures are compatible with a homology model based on the ADP/ATP carrier X-ray structure, supporting the six-helix bundle architecture of the carrier. CD and NMR spectroscopy of synthetic transmembrane peptides; homology modeling based on ADP/ATP carrier crystal structure The Italian journal of biochemistry Medium 19192628
2018 Germline loss-of-function mutations in SLC25A11 (encoding the mitochondrial 2-oxoglutarate/malate carrier) predispose to metastatic paraganglioma. Loss of SLC25A11 function (via CRISPR-Cas9 knockout in mouse chromaffin cells) produces pseudohypoxic and hypermethylator phenotypes comparable to those in SDHx- and FH-related tumors, indicating SLC25A11 acts as a tumor suppressor gene through disruption of mitochondrial metabolite transport. Whole-exome sequencing, loss of heterozygosity analysis, CRISPR-Cas9 knockout in mouse chromaffin cells with metabolic and epigenetic phenotyping Cancer research High 29431636
2019 SLC25A11 transports cytosolic NADH into mitochondria in the form of malate (as part of the malate-aspartate shuttle), and cancer cells (NSCLC and melanoma) exhibit higher cytosolic-to-mitochondrial NADH ratios and higher SLC25A11 expression than normal cells. Knockdown of SLC25A11 impairs mitochondrial ATP production and inhibits cancer cell growth, while heterozygous Slc25a11 knockout mice suppress KRAS-driven lung tumor formation. siRNA knockdown with ATP/NADH measurement, metabolite profiling, in vivo KRAS lung tumor cross-breeding model with heterozygous Slc25a11 knockout mice EBioMedicine High 30686754
2024 Neutrophil extracellular traps (NETs) decrease the stability and dimerization of SLC25A11, assessed by blue native PAGE, leading to depletion of mitochondrial glutathione (mitoGSH), which induces ferroptosis in smooth muscle cells and promotes abdominal aortic aneurysm formation. SLC25A11 functions as a mitochondrial glutathione transporter whose dimerization state controls mitoGSH levels. Blue native PAGE (SLC25A11 dimerization), western blotting/immunofluorescence, in vitro SMC ferroptosis assay, in vivo angiotensin II AAA mouse model with PAD4 KO, transmission electron microscopy Free radical biology & medicine High 38796028
2025 N-phenylmaleimide (KN612) inhibits SLC25A11 (the αKG/malate antiporter component of the malate-aspartate shuttle in GBM), reducing oxygen consumption rate, ATP levels, mitochondrial activity, and cell viability in glioblastoma tumorspheres, and decreasing stemness and invasion; in vivo orthotopic xenograft treatment reduced tumor size and prolonged survival. siRNA knockdown, pharmacological inhibition (KN612), oxygen consumption rate measurement, ATP assay, in vivo orthotopic xenograft mouse model, transcriptomic analysis Cancer cell international Medium 40405188
2025 OTUD1 deubiquitinates and stabilizes SLC25A11 protein, thereby increasing mitochondrial ROS and apoptosis in nasopharyngeal carcinoma cells; loss of OTUD1-mediated SLC25A11 stabilization enhances radioresistance, and this axis is regulated upstream by TFAP2C methylation. Co-immunoprecipitation (OTUD1-SLC25A11 interaction), deubiquitination assay, siRNA knockdown/overexpression with ROS and apoptosis readouts, in vitro and in vivo radioresistance assays Cell death & disease Medium 40664662
2025 Chronic hypoxia increases N6-methyladenosine (m6A) modification on the SLC25A11 3'UTR via METTL3, with m6A-binding protein YTHDF2 binding to the SLC25A11 3'UTR, leading to decreased SLC25A11 expression and subsequent ferroptosis and mitochondrial dysfunction in cardiomyocytes. SLC25A11 overexpression inhibits chronic hypoxia-induced ferroptosis; the METTL3 inhibitor STM2457 reverses this by restoring SLC25A11 levels. m6A methylation assay (MeRIP), YTHDF2 RIP (RNA immunoprecipitation), SLC25A11 overexpression/shRNA in cardiomyocytes, cell viability/ferroptosis assays, hypoxic mouse model Journal of the American Heart Association Medium 41404734
2025 OGC (Slc25a11) silencing in RPE cells aggravates TGF-β2-induced epithelial-to-mesenchymal transition (EMT) via pSmad2/3 upregulation dependent on PI3K/AKT signaling, and reduces mitochondrial respiration and mitoGSH; conversely, OGC overexpression attenuates EMT, cell proliferation, and migration. In vivo, OGC+/− mice show significantly augmented subretinal fibrosis after laser photocoagulation. siRNA knockdown and overexpression of OGC in ARPE-19 cells, EMT marker measurement (α-SMA, fibronectin, collagen I, E-cadherin, Slug), mitochondrial bioenergetics assay, PI3K/AKT/Smad2/3 pathway analysis, OCT and immunostaining in OGC+/− mice Aging cell Medium 41147690
2025 SLC25A11 inhibition leads to accumulation of TCA-related metabolites, loss of mitochondrial membrane potential, and mitochondrial lipid ROS accumulation. Loss of SLC25A11 reduces NRF2 expression/nuclear translocation and its interaction with ferroptosis suppressor FSP1, activating lipid peroxidation molecules ACSL4, LPCAT3, and PEBP1 to induce ferroptosis in biliary tract cancer cells. SLC25A11 knockdown/overexpression, RNA sequencing, mitochondrial membrane potential assay, lipid ROS imaging, NRF2-FSP1 co-immunoprecipitation, ACSL4/LPCAT3/PEBP1 protein expression, ferrostatin-1 rescue, in vivo tumor model Cellular & molecular biology letters Medium 41514409
2025 SLC25A11 (the mitochondrial αKG/malate antiporter) is required for KDM2A-dependent reduction of rRNA transcription: inhibition of SLC25A11 by N-phenylmaleimide or its knockdown blocks the AOA (aspartate transaminase inhibitor)-induced decrease in intracellular αKG, preventing KDM2A from demethylating H3K36me2 at the rRNA gene promoter. Supplementation with cell-permeable dimethyl-αKG restores KDM2A activity inhibited by SLC25A11 blockade, linking SLC25A11-mediated αKG export from mitochondria to epigenetic regulation of rRNA transcription. N-phenylmaleimide pharmacological inhibition of SLC25A11, siRNA knockdown of SLC25A11, intracellular ATP measurement, H3K36me2 ChIP at rRNA gene promoter, dimethyl-αKG supplementation rescue experiment in MCF-7 cells Cells Medium 41227300
2025 A forward genetic screen using an αKG biosensor identified a sequential inter-organelle pathway in which GPT2 transaminase and SLC25A11 transporter together supply nuclear αKG required for chromatin demethylation; loss of this pathway in a mouse model of GPT2 deficiency alters chromatin methylation in the developing brain. αKG transcriptional biosensor (NtcA-based), CRISPR genetic screen, GPT2-deficient mouse model, chromatin methylation analysis bioRxivpreprint Medium bio_10.1101_2025.04.06.647450

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
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 Network organization of the human autophagy system. Nature 1286 20562859
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
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
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
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
2012 The mitochondrial transporter family SLC25: identification, properties and physiopathology. Molecular aspects of medicine 492 23266187
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
2012 Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 319 22810586
2016 Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics. Cell reports 306 27342126
2020 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature 292 32322062
2022 EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3. Molecular cancer 257 35031058
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
2012 MMS19 assembles iron-sulfur proteins required for DNA metabolism and genomic integrity. Science (New York, N.Y.) 230 22678362
2016 Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function. Molecular cell 220 27499296
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
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2018 OTUB2 Promotes Cancer Metastasis via Hippo-Independent Activation of YAP and TAZ. Molecular cell 163 30472188
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2010 A functional peptidyl-tRNA hydrolase, ICT1, has been recruited into the human mitochondrial ribosome. The EMBO journal 153 20186120
2018 Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas. Cancer research 108 29431636
2019 Loss of SLC25A11 causes suppression of NSCLC and melanoma tumor formation. EBioMedicine 42 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 19 38796028
2025 N-phenylmaleimide induces bioenergetic switch and suppresses tumor growth in glioblastoma tumorspheres by inhibiting SLC25A11. Cancer cell international 4 40405188
2025 SLC25A11, a Novel Gene Associated With Carney-Stratakis Syndrome. Journal of the Endocrine Society 3 40242210
2025 Combining decitabine with radiotherapy to enhance nasopharyngeal carcinoma radiosensitivity via the TFAP2C-OTUD1-SLC25A11 axis. Cell death & disease 3 40664662
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