Affinage

SFXN4

Sideroflexin-4 · UniProt Q6P4A7

Length
337 aa
Mass
38.0 kDa
Annotated
2026-06-10
22 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SFXN4 is a mitochondrial inner membrane protein essential for respiratory chain function and erythropoiesis, with loss-of-function mutations causing mitochondrial disease accompanied by macrocytic anemia (PMID:24119684). Mechanistically, SFXN4 acts as a complex I assembly factor: it interacts with the MCIA (Mitochondrial Complex I Assembly) complex and is specifically required for assembly of the ND2 module, such that its loss produces complex I enzyme deficiency and depletion of complex I subunit proteins (PMID:35333655, PMID:31059822). SFXN4 is independently required for iron-sulfur (Fe-S) cluster biogenesis, and its loss diminishes respiratory chain complex stability, shifts metabolism toward glycolysis, perturbs the cytosolic aconitase-IRP1 switch, redistributes iron from cytosol to mitochondria, and impairs heme synthesis through reduced ferrochelatase levels and inhibited ALAS2 translation — connecting its molecular activity to the anemia phenotype (PMID:31873120). Disruption of Fe-S-dependent processes downstream of SFXN4 loss extends to DNA repair enzymes, and SFXN4 depletion sensitizes ovarian cancer cells to DNA-damaging agents and PARP inhibitors while restraining tumor growth in xenografts (PMID:36402786).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2013 High

    Established SFXN4 as a disease gene by linking its loss to mitochondrial respiratory failure and macrocytic anemia, framing it as a respiratory homeostasis factor rather than a bystander locus.

    Evidence Exome sequencing of affected individuals with reciprocal in vitro and in vivo complementation and zebrafish morpholino knockdown

    PMID:24119684

    Open questions at the time
    • No molecular mechanism for how SFXN4 supports respiration identified
    • Connection between respiratory defect and anemia not resolved at this stage
  2. 2019 Medium

    Placed SFXN4 upstream of Fe-S cluster biogenesis and iron/heme handling, explaining how its loss could simultaneously cripple respiration and erythropoiesis.

    Evidence SFXN4 knockout cell lines with Fe-S activity assays, metabolic flux analysis, and ferrochelatase/ALAS2 readouts; plus a patient muscle study with biochemical and ultrastructural complex I deficiency

    PMID:31059822 PMID:31873120

    Open questions at the time
    • Whether SFXN4 directly catalyzes Fe-S assembly or acts indirectly not distinguished
    • Mechanism linking SFXN4 to ALAS2 translational control unknown
    • Patient findings rest on a single case
  3. 2022 High

    Defined a direct molecular role for SFXN4 as a complex I assembly factor acting through the MCIA complex at the ND2 module, providing a concrete mechanism for the complex I deficiency.

    Evidence Reciprocal Co-immunoprecipitation, complexome profiling, and SFXN4 KO complex I assembly assays

    PMID:35333655

    Open questions at the time
    • How a putative transporter contributes to module assembly is unresolved
    • Relationship between the assembly role and the Fe-S/iron role not reconciled
  4. 2022 Medium

    Extended the consequences of SFXN4-dependent Fe-S biogenesis to genome maintenance and identified a therapeutic vulnerability in cancer.

    Evidence siRNA knockdown and KO with Fe-S/ROS assays, DNA repair and drug-sensitivity assays, and mouse xenograft tumor growth experiments

    PMID:36402786

    Open questions at the time
    • Which specific Fe-S DNA repair enzymes are rate-limiting not defined
    • Single-lab findings without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • The transport substrate of SFXN4 and how a single protein integrates complex I ND2-module assembly with Fe-S cluster biogenesis and iron homeostasis remain unresolved.
  • No demonstrated transported substrate for SFXN4
  • No structural model of SFXN4 within the MCIA complex
  • Mechanistic link between assembly function and iron/Fe-S function not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Complex memberships
MCIA complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 SFXN4 localizes to the mitochondrial inner membrane and is required for mitochondrial respiratory homeostasis and erythropoiesis; loss-of-function mutations cause mitochondrial respiratory defects and macrocytic anemia, demonstrated by sfxn4 knockdown in zebrafish and in vitro/in vivo complementation with patient fibroblasts. Exome sequencing, zebrafish morpholino knockdown, in vitro and in vivo complementation studies with patient fibroblasts American journal of human genetics High 24119684
2019 SFXN4 knockout reduces Fe-S cluster formation, diminishes mitochondrial respiratory chain complex stability and activity, causes a shift to glycolytic metabolism, affects the cytosolic aconitase-IRP1 switch, redistributes iron from cytosol to mitochondria, reduces ferrochelatase levels, and inhibits translation of ALAS2. SFXN4 knockout cell lines, Fe-S cluster activity assays, metabolic flux analysis (glycolysis vs. respiration), immunoblot for ferrochelatase, ALAS2 translation assay Scientific reports Medium 31873120
2022 SFXN4 functions as a complex I assembly factor that interacts with the MCIA (Mitochondrial Complex I Assembly) complex and is specifically required for assembly of the ND2 module of mitochondrial complex I. Co-immunoprecipitation, complexome profiling, SFXN4 KO cell lines with complex I assembly assays, interaction studies with MCIA complex components Proceedings of the National Academy of Sciences of the United States of America High 35333655
2022 SFXN4 knockdown in ovarian cancer cells inhibits Fe-S cluster biogenesis, leading to accumulation of excess iron and oxidative stress, and reduces activity of Fe-S-dependent DNA repair enzymes, thereby sensitizing cells to DNA-damaging agents and PARP inhibitors; SFXN4 knockout inhibits tumor growth in a mouse xenograft model. siRNA knockdown, Fe-S cluster activity assays, ROS measurements, DNA repair assays, cisplatin/PARP inhibitor sensitivity assays, mouse xenograft tumor growth experiments Scientific reports Medium 36402786
2019 SFXN4 loss-of-function mutations cause complex I enzyme activity deficiency with loss of complex I subunit proteins and ultrastructural mitochondrial abnormalities, as shown in muscle tissue from a patient with bi-allelic SFXN4 mutations. Whole-exome sequencing, mitochondrial enzyme activity assays, immunoblot for complex I subunit proteins, electron microscopy of muscle, mRNA expression analysis Mitochondrion Medium 31059822
2003 SFXN4 encodes a 305-amino acid protein with a predicted five-transmembrane-domain structure, consistent with a mitochondrial transporter, and is expressed in many tissues. cDNA cloning from human fetal brain library, sequence analysis, RT-PCR expression profiling, genomic mapping DNA sequence : the journal of DNA sequencing and mapping Low 14756423
2023 In CLPP-deficient mouse testis, SFXN4 accumulates alongside COX15 as a complex IV metal-binding assembly factor co-accumulating with heavy metals (iron, molybdenum, cobalt, manganese), suggesting SFXN4 participates in mitochondrial metal/iron handling during complex assembly. Complexome profiling (complexomics), heavy metal quantification, immunoblot validation in mouse tissue International journal of molecular sciences Low 38139332
2025 SFXN4 is implicated in mitochondrial iron regulation, heme biosynthesis, and iron-sulfur cluster assembly, with SFXN1 and SFXN3 specializing in serine transport while SFXN2 and SFXN4 specialize in iron-related functions; SFXNs share conserved transmembrane domains critical for substrate transport. Comparative genomics and literature review of family function; structural domain analysis Human genomics Low 40542427

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Macrocytic anemia and mitochondriopathy resulting from a defect in sideroflexin 4. American journal of human genetics 56 24119684
2019 Sideroflexin 4 affects Fe-S cluster biogenesis, iron metabolism, mitochondrial respiration and heme biosynthetic enzymes. Scientific reports 44 31873120
2020 Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke. Stroke 28 32693751
2022 Sideroflexin 4 is a complex I assembly factor that interacts with the MCIA complex and is required for the assembly of the ND2 module. Proceedings of the National Academy of Sciences of the United States of America 23 35333655
2003 Molecular cloning and characterization of a novel human putative transmembrane protein homologous to mouse sideroflexin associated with sideroblastic anemia. DNA sequence : the journal of DNA sequencing and mapping 20 14756423
2021 Trait correlated expression combined with eQTL and ASE analyses identified novel candidate genes affecting intramuscular fat. BMC genomics 17 34749647
2022 Hereditary myopathies associated with hematological abnormalities. Muscle & nerve 11 34985130
2022 Complementary anti-cancer pathways triggered by inhibition of sideroflexin 4 in ovarian cancer. Scientific reports 10 36402786
2019 [Prenatal onset of mitochondrial disease is associated with sideroflexin 4 deficiency]. Mitochondrion 10 31059822
2023 Comprehensive Analysis of Sideroflexin 4 in Hepatocellular Carcinoma by Bioinformatics and Experiments. International journal of medical sciences 9 37786439
2020 Interactome networks between the human respiratory syncytial virus (HRSV), the human metapneumovirus (ΗMPV), and their host: In silico investigation and comparative functional enrichment analysis. Microbial pathogenesis 8 31988005
2023 Translation Fidelity and Respiration Deficits in CLPP-Deficient Tissues: Mechanistic Insights from Mitochondrial Complexome Profiling. International journal of molecular sciences 5 38139332
2021 Transcriptome-wide Association Study Identifies Genetically Dysregulated Genes in Diabetic Neuropathy. Combinatorial chemistry & high throughput screening 5 32772906
2025 Update of the sideroflexin (SLC56) gene family. Human genomics 4 40542427
2025 Multi-omics integrative analysis reveals novel genetic loci and candidate genes for ischemic stroke. Molecular therapy. Nucleic acids 4 40777745
2022 Screening and Analysis of Potential Critical Gene in Acute Myocardial Infarction Based on a miRNA-mRNA Regulatory Network. International journal of general medicine 4 35300139
2025 Sideroflexin family genes were dysregulated and associated with tumor progression in prostate cancers. Human genomics 2 39915876
2024 Exploring the novel duo of Reticulocalbin, and Sideroflexin as future biomarker candidates for Exacerbated Chronic Obstructive Pulmonary Disease. Clinical proteomics 2 38355435
2026 Phenotypic description and functional characterization of the mitochondrial disease associated with the SFXN4 gene. Mitochondrion 0 41713566
2025 Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke. Open medicine (Warsaw, Poland) 0 40292254
2025 Expression and Clinical Significance of Sideroflexin 4 (SFXN4) in Colorectal Cancer. In vivo (Athens, Greece) 0 41167676
2025 Construction and validation of an oxidative phosphorylation-related gene signature in lung squamous cell carcinoma patients. Lung cancer management 0 41343408

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