Affinage

SLC25A40

Mitochondrial glutathione transporter SLC25A40 · UniProt Q8TBP6

Length
338 aa
Mass
38.1 kDa
Annotated
2026-04-28
12 papers in source corpus 6 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC25A40 is a mitochondrial inner membrane transporter that imports glutathione (GSH) into the mitochondrial matrix, thereby maintaining mitochondrial redox homeostasis and supporting iron-sulfur cluster protein stability. Loss of SLC25A40 decreases mitochondrial GSH levels, destabilizes iron-sulfur cluster-containing electron transport chain complexes, elevates mitochondrial and cellular ROS, and impairs LPS-stimulated cytokine production (IL-1β, IL-10) in macrophages, effects phenocopied by chemical depletion of mitochondrial GSH and partially rescued by exogenous GSH supplementation (PMID:41326555, PMID:35955707, PMID:37407483). SLC25A40 also promotes cancer cell proliferation by enhancing NADPH-dependent lipid synthesis and suppresses ferroptosis through reduction of mitochondrial ROS (PMID:40876707). A rare missense variant (p.Tyr125Cys) in SLC25A40 is genetically associated with hypertriglyceridemia in humans (PMID:24268658).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2013 Medium

    Before any functional data existed, human genetic analysis placed SLC25A40 in triglyceride metabolism by linking a rare coding variant to familial hypertriglyceridemia, establishing the first disease association for this orphan mitochondrial carrier.

    Evidence Joint linkage and whole-exome sequencing in a five-generation family plus burden testing in the Exome Sequencing Project cohort

    PMID:24268658

    Open questions at the time
    • No in vitro transport assay or reconstitution was performed
    • Mechanism linking mitochondrial transport to triglyceride levels remains unknown
    • Single-family discovery without replication in an independent cohort
  2. 2022 Medium

    The first mechanistic identity for SLC25A40 cargo was established: it functions alongside SLC25A39 in mitochondrial glutathione import, with loss of expression correlating with decreased mitochondrial GSH in vivo, resolving a longstanding gap in how GSH reaches the mitochondrial matrix.

    Evidence Mouse bile duct ligation model with mRNA/protein quantification and direct mitochondrial GSH measurement

    PMID:35955707

    Open questions at the time
    • Correlative in vivo model; no genetic knockout or direct reconstitution of GSH transport
    • Relative contributions of SLC25A39 vs. SLC25A40 to mGSH import were not separated
    • Relevance to triglyceride phenotype not addressed
  3. 2023 Medium

    Cell-based knockdown confirmed that SLC25A40 is required for mitochondrial GSH maintenance in human cells, extending the in vivo finding to a defined loss-of-function system and linking mGSH depletion to reduced cell proliferation and drug resistance.

    Evidence siRNA knockdown with mitochondrial GSH quantification and proliferation assays in K562 leukemia cells

    PMID:37407483

    Open questions at the time
    • Single cell line and single lab
    • No rescue with re-expression or GSH supplementation performed
    • Direct transport activity of SLC25A40 not reconstituted in vitro
  4. 2025 High

    A comprehensive mechanistic study resolved the downstream pathway: SLC25A40-mediated mGSH import stabilizes iron-sulfur cluster-containing ETC proteins, controls mitochondrial ROS, and is required for macrophage cytokine production, with chemical phenocopy and GSH rescue providing causal evidence for the mGSH-dependent mechanism.

    Evidence siRNA knockdown, mitochondrially-targeted GSH depletion (CDNB), GSH ester rescue, Western blot for ETC complex subunits, ROS assays, and cytokine/NLRP3 inflammasome assays in murine and human macrophages

    PMID:41326555

    Open questions at the time
    • Direct in vitro reconstitution of GSH transport by purified SLC25A40 still lacking
    • Whether ISC destabilization fully explains the cytokine phenotype versus additional mGSH-dependent mechanisms is unresolved
    • Contribution relative to SLC25A39 in macrophages not tested
  5. 2025 Medium

    SLC25A40 was linked to cancer cell fitness beyond drug resistance: it promotes NADPH-dependent lipid synthesis and suppresses ferroptosis in NSCLC, broadening its functional scope from redox maintenance to anabolic metabolism and regulated cell death.

    Evidence siRNA knockdown and overexpression in NSCLC cell lines with NADPH measurement, ferroptosis assays, mitochondrial ROS quantification, and miR-4299 regulation studies

    PMID:40876707

    Open questions at the time
    • Single-lab study; NADPH link not connected to GSH transport directly
    • Whether ferroptosis suppression is a direct consequence of mGSH import or an indirect effect via NADPH is unclear
    • In vivo tumor models not employed

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unifying mechanistic model connecting SLC25A40-mediated GSH transport to triglyceride metabolism, the relative contribution of SLC25A40 versus SLC25A39, and direct biochemical reconstitution of substrate transport remain unresolved.
  • No purified reconstitution of SLC25A40 GSH transport activity exists
  • Mechanism linking mGSH or mitochondrial redox to triglyceride regulation is unknown
  • Structural basis for substrate selectivity and distinction from SLC25A39 is uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3
Localization
GO:0005739 mitochondrion 5
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-168256 Immune System 1 R-HSA-5357801 Programmed Cell Death 1
Partners
SLC25A39

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 A missense variant in SLC25A40 (c.374A>G, p.Tyr125Cys) located just outside the second helical transmembrane region of the inner mitochondrial membrane transport protein was identified as significantly associated with hypertriglyceridemia, placing SLC25A40 in a previously undescribed pathway for triglyceride regulation. Joint linkage and association analysis with whole-exome sequencing in a five-generation family; whole-gene burden testing in Exome Sequencing Project cohort American journal of human genetics Medium 24268658
2022 SLC25A40 (together with SLC25A39) functions in mitochondrial glutathione (mGSH) import from the cytoplasm; loss of Slc25a39/40 expression in mouse kidneys (via bile duct ligation) correlated with a significant decrease in mGSH levels, supporting its role in maintaining the mitochondrial redox state. Mouse bile duct ligation model with mRNA/protein quantification and mitochondrial GSH measurement; LPS-treated mice and KMRC-1 cell TLR4/RAGE signaling studies International journal of molecular sciences Medium 35955707
2023 SLC25A40 knockdown in human leukemia K562 cells significantly decreased mitochondrial glutathione concentration and reduced cell proliferation, demonstrating that SLC25A40 supports mGSH import and thereby contributes to drug resistance and cell survival. siRNA knockdown with mitochondrial GSH quantification and cell proliferation assay in K562/ADM cells Biological & pharmaceutical bulletin Medium 37407483
2025 SLC25A40 acts as a mitochondrial glutathione transporter in macrophages; siRNA-mediated knockdown destabilized iron-sulfur cluster (ISC)-rich electron transport chain (ETC) proteins, elevated mitochondrial and cellular ROS, induced GSH biosynthesis genes (Gclc, Gclm), and diminished LPS-stimulated IL-1β and IL-10 production at the transcriptional level, as well as mature IL-1β after NLRP3 activation. Depletion of mGSH with mitochondrially-targeted CDNB phenocopied these effects, and cell-permeable GSH ester supplementation partially rescued pro-IL-1β production. siRNA knockdown, mitochondrially-targeted chemical depletion of GSH, GSH ester rescue, Western blot for ETC proteins, ROS assays, cytokine quantification, NLRP3 inflammasome activation assays in murine and human macrophages Scientific reports High 41326555
2025 SLC25A40 promotes NSCLC cell proliferation by enhancing NADPH-mediated lipid synthesis and suppresses ferroptosis by decreasing mitochondrial ROS accumulation; silencing SLC25A40 inhibited proliferation and induced ferroptosis, while overexpression had the opposite effect. Elevated SLC25A40 expression in NSCLC was linked to decreased miR-4299. siRNA knockdown and overexpression in NSCLC cell lines with proliferation assays, ferroptosis assays, NADPH measurement, mitochondrial ROS quantification, and miR-4299 regulation studies Experimental cell research Medium 40876707
2025 SLC25A40 was identified as a binding partner of the natural compound ophiobolin A in EMT-positive breast cancer cells; engagement of SLC25A40 by ophiobolin A was associated with alterations in mitochondrial glutathione production and mitochondrial iron concentrations. Proteomic pulldown/interaction studies identifying proteins interacting with ophiobolin A in EMT(+) cells; trans-mitochondrial cybrid experiments bioRxiv (preprint)preprint Low bio_10.1101_2025.04.08.647828

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Cone survival despite rod degeneration in XOPS-mCFP transgenic zebrafish. Investigative ophthalmology & visual science 83 16303977
2011 Molecular interactions of mussel protective coating protein, mcfp-1, from Mytilus californianus. Biomaterials 60 22138031
2012 Mussel foot protein-1 (mcfp-1) interaction with titania surfaces(). Journal of materials chemistry 40 23100857
2013 Joint linkage and association analysis with exome sequence data implicates SLC25A40 in hypertriglyceridemia. American journal of human genetics 36 24268658
2007 Heterologous expression of Mytilus californianus foot protein three (Mcfp-3) in Kluyveromyces lactis. Protein expression and purification 12 17923416
2022 Slc25a39 and Slc25a40 Expression in Mice with Bile Duct Ligation or Lipopolysaccharide Treatment. International journal of molecular sciences 11 35955707
2023 SLC25A40 Facilitates Anticancer Drug Resistance in Human Leukemia K562 Cells. Biological & pharmaceutical bulletin 5 37407483
2019 Chemotaxis of Pseudomonas putida F1 to Alcohols Is Mediated by the Carboxylic Acid Receptor McfP. Applied and environmental microbiology 5 31471307
2021 Phenotypic Consequences of SLC25A40-ABCB1 Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer. Cancers 4 34830797
2021 Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort. BMC medical genomics 2 33407432
2025 SLC25A40 promotes NSCLC growth by enhancing NADPH-mediated lipid synthesis and suppressing ROS accumulation-induced ferroptosis. Experimental cell research 0 40876707
2025 Mitochondrial glutathione transporter SLC25A40 regulates macrophage cytokine production. Scientific reports 0 41326555