Affinage

SLC25A51

Mitochondrial nicotinamide adenine dinucleotide transporter SLC25A51 · UniProt Q9H1U9

Length
297 aa
Mass
33.7 kDa
Annotated
2026-06-10
17 papers in source corpus 12 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

SLC25A51 (MCART1) is the mammalian mitochondrial inner-membrane carrier that selectively imports oxidized NAD+ into the mitochondrial matrix, establishing the supply of NAD+ that drives mitochondrial redox metabolism (PMID:32906142, PMID:33087354). Its identity as a NAD+ transporter rests on convergent evidence: loss of SLC25A51 selectively depletes mitochondrial (not whole-cell) NAD+ and abolishes NAD+ uptake into isolated mitochondria, while overexpression of SLC25A51 or its paralogue SLC25A52 restores uptake and rescues yeast mitochondria lacking endogenous NAD+ transporters (PMID:32906142). By controlling matrix NAD+ availability, SLC25A51 sustains TCA cycle flux, ETC complex I activity, and mitochondrial respiration (PMID:33087354), and AML cells upregulate it to maintain oxidative metabolism from multiple fuels (PMID:38354740). Mechanistically, transport is cardiolipin-assisted and ligand-led: cardiolipin engages three exterior sites required for activity, an electrostatic interaction between the nicotinamide ring and a negatively charged pore patch governs selectivity for NAD+ over NADH, and interior residue E132 weakens a salt-bridge matrix gate to initiate transport (PMID:37575034). Downstream, matrix NAD+ delivered by SLC25A51 is required for SIRT3 deacetylase activity, so its loss elevates mitochondrial protein acetylation, impairing SIRT3 targets including IDH2, ACADL, and the proline-biosynthetic enzyme P5CS (PMID:35932995, PMID:37419986). Loss of mitochondrial import also redistributes NAD+ to the nucleus and cytoplasm, increasing PARP1-mediated ADP-ribosylation and single-strand break repair and reducing PARP-inhibitor sensitivity (PMID:37587695). SLC25A51 abundance is set transcriptionally by repression from BACH1 (PMID:40312332) and post-translationally by OGDHC-mediated K264 succinylation that stabilizes the protein (PMID:41616775), and its activity influences cellular senescence and systemic metabolism in beta cells and adipose tissue (PMID:42015379).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2020 High

    Established the long-sought identity of the mammalian mitochondrial NAD+ transporter, resolving how the matrix obtains NAD+ when no eukaryotic carrier had been defined.

    Evidence Mitochondrial NAD+ quantification, in vitro NAD+ uptake into isolated mitochondria, and functional complementation in yeast lacking endogenous NAD+ transporters in KO/OE cells

    PMID:32906142 PMID:33087354 PMID:33262325

    Open questions at the time
    • Structural basis of transport not resolved at this stage
    • Did not define transport mechanism or selectivity determinants
  2. 2020 High

    Connected the transport function to downstream bioenergetics, showing that mitochondrial NAD+ import is rate-limiting for oxidative metabolism rather than a passive housekeeping process.

    Evidence TCA flux analysis, Seahorse respirometry, ETC complex I activity assays, and in vitro uptake in MCART1-null cells

    PMID:33087354

    Open questions at the time
    • Did not address how transporter abundance is regulated
    • Tissue- and disease-specific roles not examined
  3. 2023 Medium

    Defined the molecular transport mechanism, explaining how the carrier achieves NAD+ selectivity and gates substrate passage across the inner membrane.

    Evidence Molecular dynamics simulations with lipid bilayer reconstitution plus site-directed mutagenesis of cardiolipin sites and gating residues with functional transport assays

    PMID:37575034

    Open questions at the time
    • No experimental high-resolution structure reported
    • MD-derived gating model not independently replicated
  4. 2022 Medium

    Linked SLC25A51-supplied matrix NAD+ to SIRT3 function, establishing a regulatory consequence of import on mitochondrial protein acetylation in liver.

    Evidence shRNA knockdown in hepatocytes and mouse liver with mitochondrial NAD+ quantification, SIRT3-target acetylation (IDH2, ACADL) westerns, and OCR measurement

    PMID:35932995

    Open questions at the time
    • Single lab
    • Direct demonstration that acetylation changes are SIRT3-dependent in vivo not fully resolved
  5. 2023 Medium

    Extended the SIRT3 axis to a specific metabolic output and identified a pharmacological inhibitor, showing import loss impairs proline biosynthesis via P5CS hyperacetylation.

    Evidence KO cell lines with P5CS enzymatic activity assay, acetylation and proline measurements, and fludarabine phosphate drug-binding assays

    PMID:37419986

    Open questions at the time
    • Specificity of fludarabine phosphate for SLC25A51 versus other targets not fully delineated
    • Single lab
  6. 2023 Medium

    Revealed a cross-compartment consequence of transport loss, showing mitochondrial NAD+ import competes with nuclear NAD+-dependent PARP1 signaling and DNA repair.

    Evidence KO cells with subcellular NAD+ measurement, ADP-ribosylation and single-strand break repair assays, PARP1 chromatin retention, and PARP-inhibitor sensitivity in breast cancer cells

    PMID:37587695

    Open questions at the time
    • Mechanism of NAD+ redistribution between compartments not fully defined
    • Single lab
  7. 2024 Medium

    Demonstrated a cancer dependency, showing AML cells upregulate SLC25A51 to sustain oxidative metabolism from multiple fuels.

    Evidence Isotope-tracing metabolic flux analysis with shRNA depletion, orthotopic xenografts, and combination treatment with 5-azacytidine in vivo

    PMID:38354740

    Open questions at the time
    • Generalizability beyond AML not established
    • Single lab
  8. 2025 Medium

    Identified transcriptional control of the transporter, placing SLC25A51 under repression by BACH1 with functional consequences for endothelial proliferation.

    Evidence Dual-luciferase reporter, EMSA, BACH1-KO mice, shRNA rescue, and ETC complex activity assays in HUVECs

    PMID:40312332

    Open questions at the time
    • Single lab
    • Whether BACH1 regulation operates in other tissues unknown
  9. 2026 Medium

    Defined post-translational control of transporter stability, identifying OGDHC-mediated K264 succinylation as a stabilizing modification exploited for synthetic lethality in KRAS-mutant AML.

    Evidence MS identification of K264 succinylation, mutagenesis, compound 615 treatment, stability and mitochondrial NAD+ assays, and in vivo AML models

    PMID:41616775

    Open questions at the time
    • Single lab, abstract-level description
    • Selectivity of compound 615 between SLC25A51 and SDH not fully characterized
  10. 2026 Medium

    Established systemic physiological roles, showing SLC25A51 controls mitochondrial NAD+ and oxidative function in adipose tissue and beta cells with consequences for aging metabolism.

    Evidence Tissue-specific KO and OE mouse models with mitochondrial NAD+ quantification, respirometry, fatty acid oxidation, adiponectin, and senescence/metabolic phenotyping

    PMID:40642112 PMID:42015379

    Open questions at the time
    • Beta-cell senescence findings remain a preprint not yet peer-reviewed
    • Mechanism linking NRF2 to SLC25A51 in senescence not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • An experimental high-resolution structure of SLC25A51 in substrate-bound and gated states is still needed to confirm the MD-derived transport and selectivity model.
  • No experimental structure in the corpus
  • Conformational cycle of the carrier inferred only from simulation

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 2
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-382551 Transport of small molecules 2

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 SLC25A51 (MCART1) is a mammalian mitochondrial NAD+ transporter: loss of SLC25A51 decreases mitochondrial (but not whole-cell) NAD+ content and blocks NAD+ uptake into isolated mitochondria; overexpression of SLC25A51 or its paralogue SLC25A52 increases mitochondrial NAD+ levels and restores NAD+ uptake into yeast mitochondria lacking endogenous NAD+ transporters. NAD+ measurement in isolated mitochondria, NAD+ uptake assays in isolated mitochondria from KO/OE cells, functional complementation in yeast lacking endogenous NAD+ transporters, loss-of-function respiratory phenotype Nature High 32906142
2020 MCART1/SLC25A51 loss causes large decreases in TCA cycle flux, mitochondrial respiration, ETC complex I activity, and mitochondrial NAD+/NADH levels; isolated mitochondria from MCART1-null cells show greatly decreased NAD uptake in vitro, while overexpression increases it; MCART1 and yeast NDT1 can functionally complement each other. MCART1-null cell lines, TCA cycle flux analysis, Seahorse respirometry, ETC complex I activity assay, in vitro NAD uptake into isolated mitochondria, yeast functional complementation, gene essentiality co-essentiality mining Science advances High 33087354
2020 Genetic interaction network analysis placed SLC25A51 as an enabler of mitochondrial NAD import, with strong genetic interactions linking it to mitochondrial respiration and redox metabolism; metabolomics and genomics confirmed its role in NAD import. Genetic interaction mapping across SLC genes, metabolomics, genomics, epistasis analysis Nature communications High 33262325
2023 SLC25A51 selectively transports oxidized NAD+ (not NADH); cardiolipin binds to three distinct exterior sites on SLC25A51 and mutations at these sites impair both cardiolipin binding and transporter activity; a single salt bridge controls matrix gate formation; an electrostatic interaction between the charged nicotinamide ring of NAD+ and a negatively charged pore patch governs selectivity; interior residue E132 interacts with NAD+ to dynamically weaken the salt bridge gate, initiating ligand-led transport. Molecular dynamics simulations with reconstitution into lipid bilayers, site-directed mutagenesis of cardiolipin-binding sites and gating residues, functional transport assays EMBO reports Medium 37575034
2022 Knockdown of Slc25a51 in hepatocytes and mouse liver decreases mitochondrial NAD+ levels and reduces SIRT3 deacetylase activity, evidenced by increased acetylation of SIRT3 target proteins IDH2 and ACADL; Slc25a51 knockdown also reduces mitochondrial oxygen consumption rate; fasting induces hepatic Slc25a51 expression and its circadian expression is disrupted in BMAL1 liver-specific knockout mice. shRNA-mediated knockdown in hepatocytes and mouse liver, mitochondrial NAD+ quantification, SIRT3 target acetylation (IDH2, ACADL) by western blot, Seahorse mitochondrial OCR, liver-specific BMAL1 KO mice Metabolism: clinical and experimental Medium 35932995
2023 Loss of SLC25A51 elevates mitochondrial protein acetylation due to SIRT3 dysfunction, which impairs P5CS enzymatic activity (the key enzyme in proline biosynthesis) and reduces intracellular proline content; fludarabine phosphate binds to and inhibits SLC25A51, causing mitochondrial NAD+ decrease and protein hyperacetylation. SLC25A51 KO cell lines, mitochondrial protein acetylation assays, P5CS enzymatic activity assay, proline quantification, drug-binding assay with fludarabine phosphate, cell proliferation assays Cell death and differentiation Medium 37419986
2023 Absence of SLC25A51 leads to increased NAD+ concentration in both cytoplasm and nucleus (not due to upregulation of the salvage pathway), resulting in increased PARP1-mediated nuclear ADP-ribosylation, faster repair of single-strand DNA lesions, reduced PARP1 chromatin retention, and decreased sensitivity to PARP inhibitors in breast cancer cells. SLC25A51 KO cells, subcellular NAD+ measurement, ADP-ribosylation assays, single-strand DNA damage repair assays, PARP1 chromatin retention assay, PARP inhibitor sensitivity assays Nucleic acids research Medium 37587695
2024 SLC25A51 selectively imports oxidized NAD+ into the mitochondrial matrix; depletion of SLC25A51 in AML cells shunts metabolic flux away from mitochondrial oxidative pathways without increasing glycolytic flux, and decouples the mitochondrial NAD+/NADH ratio, indicating that AML cells upregulate SLC25A51 to sustain oxidative reactions from multiple fuels for a proliferative advantage. Metabolic flux analysis (isotope tracing), SLC25A51 depletion by shRNA, orthotopic xenograft models, apoptosis assays, combination treatment with 5-azacytidine in vivo Cell metabolism Medium 38354740
2025 BACH1 transcriptionally represses SLC25A51; BACH1 deficiency activates SLC25A51 transcription (confirmed by dual-luciferase reporter and EMSA), promoting mitochondrial NAD+ transport and restoring ETC complex I, II, and IV activities; shRNA knockdown of SLC25A51 reverses the pro-proliferative effect of BACH1 deficiency on endothelial cells. Dual-luciferase reporter assay, EMSA, BACH1-knockout mice, shRNA knockdown of SLC25A51, ETC complex activity assays, HUVEC proliferation assays, proteomics/transcriptomics Molecular medicine (Cambridge, Mass.) Medium 40312332
2026 KRAS-mutant AML cells exhibit reduced 2-oxoglutarate dehydrogenase complex (OGDHC)-mediated succinylation of SLC25A51 at K264, a modification that stabilizes the transporter; reduced succinylation destabilizes SLC25A51, creating a synthetic lethal vulnerability exploited by compound 615, which inhibits SLC25A51 and succinate dehydrogenase simultaneously to cause catastrophic mitochondrial NAD+ depletion specifically in KRAS-mutant cells. Mass spectrometry identification of K264 succinylation, mutagenesis, compound 615 treatment, SLC25A51 stability assays, mitochondrial NAD+ measurement, in vivo AML models Cell metabolism Medium 41616775
2025 Overexpression of SLC25A51 (but not a transport-dead mutant) induces senescence markers in beta cells; beta-cell-specific deletion of SLC25A51 reduces p16INK4a levels, lowers circulating insulin and glucose levels, and improves insulin sensitivity; NRF2 is implicated as a transcriptional regulator of SLC25A51 upregulation during senescence. Beta-cell-specific Slc25a51 KO mice, SLC25A51 overexpression with transport-dead mutant control, p16INK4a measurement, glucose/insulin tolerance tests, senescence markers bioRxivpreprint Medium 40642112
2026 Adipocyte-specific deletion of Slc25a51 markedly reduces adipose tissue mitochondrial NAD+ levels and impairs mitochondrial respiratory function, fatty acid oxidation capacity, and adiponectin production, leading to age-associated obesity, insulin resistance, and hepatosteatosis; adipocyte-specific overexpression protects against obesity and insulin resistance caused by aging. Adipocyte-specific Slc25a51 KO and OE mouse models, mitochondrial NAD+ quantification, respirometry, fatty acid oxidation assays, adiponectin measurement, metabolic phenotyping Aging cell Medium 42015379

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 SLC25A51 is a mammalian mitochondrial NAD+ transporter. Nature 245 32906142
2020 MCART1/SLC25A51 is required for mitochondrial NAD transport. Science advances 162 33087354
2020 Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import. Nature communications 107 33262325
2024 SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells. Cell metabolism 33 38354740
2022 The mitochondrial NAD+ transporter SLC25A51 is a fasting-induced gene affecting SIRT3 functions. Metabolism: clinical and experimental 29 35932995
2022 Overexpression of SLC25A51 promotes hepatocellular carcinoma progression by driving aerobic glycolysis through activation of SIRT5. Free radical biology & medicine 28 35182732
2023 SLC25A51 promotes tumor growth through sustaining mitochondria acetylation homeostasis and proline biogenesis. Cell death and differentiation 27 37419986
2023 Absence of mitochondrial SLC25A51 enhances PARP1-dependent DNA repair by increasing nuclear NAD+ levels. Nucleic acids research 22 37587695
2023 Dynamics of SLC25A51 reveal preference for oxidized NAD+ and substrate led transport. EMBO reports 15 37575034
2025 BACH1 deficiency improves placental angiogenesis via SLC25A51-mediated mitochondrial NAD+ transport in intrahepatic cholestasis of pregnancy. Molecular medicine (Cambridge, Mass.) 3 40312332
2021 Differential levels of CHMP2B, LLPH, and SLC25A51 proteins in secondary renal amyloidosis. Expert review of proteomics 2 33583303
2026 Nicotinamide riboside enhances liver regeneration via the MCART1/ASB3 axis in obesity-compromised rats. Hepatology communications 0 41493825
2026 Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML. Cell metabolism 0 41616775
2026 Targeting miR-4653-3p/SLC25A51/SIRT3 axis to induce synthetic lethality in ARID1A-deficient colorectal cancer via blockade of DNA repair. Journal of translational medicine 0 41639843
2026 The Mitochondrial NAD Transporter SLC25A51 in Adipocytes Regulates Adipose Tissue Mitochondrial Function and Systemic Metabolism During Aging. Aging cell 0 42015379
2026 SLC25A51 mRNA-LNP Armors T Cells with Mitochondrial Fitness in Cancer Treatment. ACS applied materials & interfaces 0 42226663
2025 The mitochondrial NAD transporter SLC25A51 is a modulator of beta cell senescence and type 2 diabetes. bioRxiv : the preprint server for biology 0 40642112

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