SLC25A28

Summary

SLC25A28 (solute carrier family 25 member 28, HGNC:23472) is a protein-coding gene on chromosome 10q24.2, encoding Mitoferrin-2 (Q96A46). Mitochondrial iron transporter that mediates iron uptake. It is a selective cancer dependency (DepMap: 25.8% of cell lines).

Predicted to enable ferrous iron transmembrane transporter activity. Predicted to be involved in iron import into the mitochondrion. Located in mitochondrion.

Source: NCBI Gene 81894 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 37 total
• Cancer dependency (DepMap): dependent in 25.8% of screened cell lines
• MANE Select transcript: NM_031212

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23472
Approved symbol	SLC25A28
Name	solute carrier family 25 member 28
Location	10q24.2
Locus type	gene with protein product
Status	Approved
Aliases	MRS3/4, MRS4L
Ensembl gene	ENSG00000155287
Ensembl biotype	protein_coding
OMIM	609767
Entrez	81894

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000370495, ENST00000434701, ENST00000496035, ENST00000700247, ENST00000700248, ENST00000700249, ENST00000700250, ENST00000700251, ENST00000700252, ENST00000700253, ENST00000913498, ENST00000966520

RefSeq mRNA: 1 — MANE Select: NM_031212 NM_031212

CCDS: CCDS41559

Canonical transcript exons

ENST00000370495 — 4 exons

Exon	Start	End
ENSE00001452862	99620045	99620439
ENSE00003259768	99610522	99611366
ENSE00003633917	99613696	99613924
ENSE00003637917	99612543	99612599

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 98.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.3949 / max 215.6569, expressed in 1780 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110988	9.2569	1779
110991	0.0873	31
110990	0.0377	21
110989	0.0130	3

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	98.28	gold quality
right testis	UBERON:0004534	98.20	gold quality
mucosa of stomach	UBERON:0001199	98.00	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.85	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.83	gold quality
lower esophagus	UBERON:0013473	97.82	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.75	gold quality
granulocyte	CL:0000094	97.74	gold quality
tibial nerve	UBERON:0001323	97.63	gold quality
right lung	UBERON:0002167	97.53	gold quality
lower esophagus mucosa	UBERON:0035834	97.50	gold quality
left ovary	UBERON:0002119	97.48	gold quality
endocervix	UBERON:0000458	97.43	gold quality
right ovary	UBERON:0002118	97.39	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.36	gold quality
left uterine tube	UBERON:0001303	97.35	gold quality
cerebellar hemisphere	UBERON:0002245	97.34	gold quality
skin of abdomen	UBERON:0001416	97.29	gold quality
cerebellar cortex	UBERON:0002129	97.28	gold quality
body of pancreas	UBERON:0001150	97.26	gold quality
nucleus accumbens	UBERON:0001882	97.23	gold quality
right coronary artery	UBERON:0001625	97.18	gold quality
right frontal lobe	UBERON:0002810	97.15	gold quality
ectocervix	UBERON:0012249	97.14	gold quality
minor salivary gland	UBERON:0001830	97.10	gold quality
apex of heart	UBERON:0002098	97.10	gold quality
upper lobe of left lung	UBERON:0008952	97.09	gold quality
body of uterus	UBERON:0009853	97.06	gold quality
body of stomach	UBERON:0001161	97.03	gold quality
tibial artery	UBERON:0007610	97.03	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.76

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

31 targeting SLC25A28, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-196A-3P	99.19	67.34	1204
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6768-3P	99.14	67.38	1319
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-6742-3P	97.95	64.50	1490
HSA-MIR-12127	97.93	66.67	793
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-558	97.50	67.16	977
HSA-MIR-2278	97.30	66.19	1130
HSA-MIR-7973	96.48	65.54	502
HSA-MIR-4484	96.35	64.08	382
HSA-MIR-3914	94.91	65.77	643

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 25.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 2)

• Mitoferrin-2-dependent mitochondrial iron uptake sensitizes human head and neck squamous carcinoma cells to photodynamic therapy (PMID:23135267)
• Compares and contrasts all the known human SLC25A* genes and includes functional information. (PMID:23266187)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc25a28	ENSDARG00000052994
mus_musculus	Slc25a28	ENSMUSG00000040414
rattus_norvegicus	Slc25a28	ENSRNOG00000016751

Paralogs (49): SLC25A13 (ENSG00000004864), SLC25A5 (ENSG00000005022), SLC25A39 (ENSG00000013306), SLC25A40 (ENSG00000075303), SLC25A3 (ENSG00000075415), SLC25A43 (ENSG00000077713), SLC25A24 (ENSG00000085491), SLC25A1 (ENSG00000100075), SLC25A17 (ENSG00000100372), SLC25A14 (ENSG00000102078), SLC25A15 (ENSG00000102743), SLC25A11 (ENSG00000108528), UCP1 (ENSG00000109424), SLC25A36 (ENSG00000114120), SLC25A12 (ENSG00000115840), SLC25A2 (ENSG00000120329), SLC25A51 (ENSG00000122696), SLC25A16 (ENSG00000122912), SLC25A35 (ENSG00000125434), SLC25A19 (ENSG00000125454), SLC25A23 (ENSG00000125648), SLC25A47 (ENSG00000140107), SLC25A52 (ENSG00000141437), SLC25A38 (ENSG00000144659), SLC25A26 (ENSG00000144741), SLC25A48 (ENSG00000145832), SLC25A37 (ENSG00000147454), SLC25A25 (ENSG00000148339), SLC25A31 (ENSG00000151475), SLC25A4 (ENSG00000151729), SLC25A27 (ENSG00000153291), SLC25A44 (ENSG00000160785), SLC25A45 (ENSG00000162241), SLC25A34 (ENSG00000162461), SLC25A32 (ENSG00000164933), SLC25A6 (ENSG00000169100), SLC25A33 (ENSG00000171612), SLC25A30 (ENSG00000174032), UCP3 (ENSG00000175564), UCP2 (ENSG00000175567)

Protein

Protein identifiers

Mitoferrin-2 — Q96A46 (reviewed: Q96A46)

Alternative names: Mitochondrial RNA-splicing protein 3/4 homolog, Mitochondrial iron transporter 2, Solute carrier family 25 member 28

All UniProt accessions (6): Q96A46, A0A8V8TPH6, A0A8V8TQ16, A0A8V8TQS6, A0A8V8TR30, X6RFA8

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial iron transporter that mediates iron uptake. Probably required for heme synthesis of hemoproteins and Fe-S cluster assembly in non-erythroid cells.

Subcellular location. Mitochondrion inner membrane Mitochondrion inner membrane.

Tissue specificity. Ubiquitous. Expressed in placenta, lung, kidney, pancreas, liver, brain, skeletal muscle and heart.

Similarity. Belongs to the mitochondrial carrier (TC 2.A.29) family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96A46-1	1	yes
Q96A46-2	2
Q96A46-3	3

RefSeq proteins (1): NP_112489* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018108	MCP_transmembrane	Repeat
IPR023395	MCP_dom_sf	Homologous_superfamily

Pfam: PF00153

Catalyzed reactions (Rhea), 1 shown:

• Fe(2+)(in) = Fe(2+)(out) (RHEA:28486)

UniProt features (17 total): transmembrane region 6, splice variant 3, repeat 3, region of interest 2, compositionally biased region 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96A46-F1	74.32	0.26

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1362409	Mitochondrial iron-sulfur cluster biogenesis
R-HSA-1430728	Metabolism

MSigDB gene sets: 240 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, PAX4_01, GOBP_TRANSITION_METAL_ION_TRANSPORT, FOXO4_01, FOXO1_01, GOBP_IRON_ION_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, PAX8_B, TCF4_Q5, IRF7_01, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, GOCC_MITOCHONDRIAL_ENVELOPE, AACTTT_UNKNOWN, RYTTCCTG_ETS2_B, YRTCANNRCGC_UNKNOWN

GO Biological Process (4): iron import into the mitochondrion (GO:0048250), monoatomic ion transport (GO:0006811), iron ion transport (GO:0006826), iron ion transmembrane transport (GO:0034755)

GO Molecular Function (2): ferrous iron transmembrane transporter activity (GO:0015093), iron ion transmembrane transporter activity (GO:0005381)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial membrane (GO:0031966), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
iron ion transmembrane transport	2
intercellular transport	1
transport	1
transition metal ion transport	1
iron ion transport	1
monoatomic cation transmembrane transport	1
iron ion transmembrane transporter activity	1
transition metal ion transmembrane transporter activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

944 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC25A28	ABCB10	Q9NRK6	982
SLC25A28	ABCB8	Q9NUT2	821
SLC25A28	FECH	P22830	801
SLC25A28	MTCH1	Q9NZJ7	768
SLC25A28	FXN	Q16595	758
SLC25A28	ABCB7	O75027	726
SLC25A28	MTCH2	Q9Y6C9	692
SLC25A28	NFS1	Q9Y697	663
SLC25A28	ISCU	Q9H1K1	632
SLC25A28	TFRC	P02786	632
SLC25A28	IREB2	P48200	623
SLC25A28	SLC11A2	P49281	623
SLC25A28	ACO1	P21399	602
SLC25A28	SLC40A1	Q9NP59	562
SLC25A28	LYRM4	Q9HD34	561

IntAct

11 interactions, top by confidence:

A	B	Type	Score
SLC15A1	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC2A12	METTL15	psi-mi:“MI:0914”(association)	0.530
PDCD1	RTL8C	psi-mi:“MI:0914”(association)	0.530
SLC25A28	BDKRB1	psi-mi:“MI:0915”(physical association)	0.370
PDCD1	TMEM223	psi-mi:“MI:0914”(association)	0.350
GPR182	METTL15	psi-mi:“MI:0914”(association)	0.350
GPR12	TLCD2	psi-mi:“MI:0914”(association)	0.350
SLC2A9	HIP1R	psi-mi:“MI:0914”(association)	0.350

BioGRID (40): SLC25A28 (Affinity Capture-MS), SLC25A28 (Affinity Capture-MS), SLC25A28 (Affinity Capture-MS), ALDH1B1 (Affinity Capture-MS), ATP1A1 (Affinity Capture-MS), ATP1B3 (Affinity Capture-MS), ATP6V1H (Affinity Capture-MS), CLPB (Affinity Capture-MS), COG5 (Affinity Capture-MS), DNAJB6 (Affinity Capture-MS), DPM1 (Affinity Capture-MS), ETFA (Affinity Capture-MS), FARSA (Affinity Capture-MS), GCDH (Affinity Capture-MS), HAX1 (Affinity Capture-MS)

ESM2 similar proteins: A0JN87, A6QR09, F1R4U0, F1RFX9, O22261, O43772, O43808, O70579, O77792, O95258, O97562, O97649, P55851, P55916, P56499, P56501, P70406, P97521, Q08DK4, Q287T7, Q3SZI5, Q4V9P0, Q5R5A8, Q5RD81, Q5RFB7, Q5U680, Q5ZKP7, Q641C8, Q66H23, Q6DG32, Q6GLA2, Q6IZB5, Q70HW3, Q8BMG8, Q8HXY2, Q8R0Z5, Q920G8, Q922G0, Q95J75, Q96A46

Diamond homologs: A0A1D6N272, A1DI57, A2A3V2, A2ASZ8, A2CEQ0, A2R5A0, A3LVX1, A4RF23, A5DIS9, A5DX39, A6RF73, A6SL61, A6ZV78, A7ER02, A7TDX5, B4F8I5, B4FIJ0, B8ZHC9, F4JU70, O04200, O04619, O22261, O43808, O59674, O60029, O70579, O94370, O97649, P04710, P0C546, P10861, P16260, P16261, P25874, P29518, P53257, P55916, Q01888, Q05AQ3, Q08DK7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

37 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

986 predictions. Top by Δscore:

Variant	Effect	Δscore
10:99611457:A:T	acceptor_gain	1.0000
10:99611459:CCAA:C	acceptor_gain	1.0000
10:99611460:C:T	acceptor_gain	1.0000
10:99611462:A:AC	acceptor_gain	1.0000
10:99611467:A:AC	acceptor_gain	1.0000
10:99613740:AATGT:A	donor_gain	1.0000
10:99613753:A:C	donor_gain	1.0000
10:99613836:AGGC:A	donor_gain	1.0000
10:99613851:ATAAT:A	donor_gain	1.0000
10:99611413:G:T	acceptor_gain	0.9900
10:99611451:C:CT	acceptor_gain	0.9900
10:99611452:A:T	acceptor_gain	0.9900
10:99611456:C:CT	acceptor_gain	0.9900
10:99611460:CAA:C	acceptor_gain	0.9900
10:99611461:A:T	acceptor_gain	0.9900
10:99611462:A:C	acceptor_gain	0.9900
10:99611467:A:C	acceptor_gain	0.9900
10:99612537:CATTA:C	donor_loss	0.9900
10:99612538:ATTAC:A	donor_loss	0.9900
10:99612539:TTA:T	donor_loss	0.9900
10:99612540:TA:T	donor_loss	0.9900
10:99612541:AC:A	donor_loss	0.9900
10:99612542:C:CT	donor_loss	0.9900
10:99612599:CCTGC:C	acceptor_loss	0.9900
10:99612600:C:A	acceptor_loss	0.9900
10:99612601:T:A	acceptor_loss	0.9900
10:99613156:A:AC	donor_gain	0.9900
10:99613157:C:CC	donor_gain	0.9900
10:99613740:A:AC	donor_gain	0.9900
10:99613741:A:C	donor_gain	0.9900

AlphaMissense

2351 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:99610917:A:G	W343R	1.000
10:99610917:A:T	W343R	1.000
10:99611086:T:A	K286N	1.000
10:99611086:T:G	K286N	1.000
10:99611120:G:T	A275D	1.000
10:99613769:A:C	F149L	1.000
10:99613769:A:T	F149L	1.000
10:99613771:A:G	F149L	1.000
10:99610925:G:T	A340D	0.999
10:99610952:C:A	R331I	0.999
10:99610964:C:T	G327E	0.999
10:99610965:C:A	G327W	0.999
10:99610965:C:G	G327R	0.999
10:99610965:C:T	G327R	0.999
10:99611074:G:C	N290K	0.999
10:99611074:G:T	N290K	0.999
10:99611078:A:G	L289P	0.999
10:99611081:A:G	L288P	0.999
10:99611087:T:A	K286I	0.999
10:99611088:T:C	K286E	0.999
10:99611089:G:C	C285W	0.999
10:99611090:C:T	C285Y	0.999
10:99611091:A:G	C285R	0.999
10:99611096:T:A	D283V	0.999
10:99611096:T:C	D283G	0.999
10:99611097:C:G	D283H	0.999
10:99611102:G:C	P281R	0.999
10:99611102:G:T	P281Q	0.999
10:99611117:G:T	A276D	0.999
10:99611126:G:T	A273D	0.999

dbSNP variants (sampled 300 via entrez): RS1000008686 (10:99621989 G>T), RS1000122077 (10:99632335 C>T), RS1000200706 (10:99640979 G>T), RS1000204129 (10:99634223 A>G), RS1000279297 (10:99615286 G>A,C), RS1000365744 (10:99648063 A>C), RS1000378129 (10:99655087 A>C), RS1000408749 (10:99632821 C>A,T), RS1000515694 (10:99637643 G>A), RS1000568083 (10:99637904 A>G), RS1000587564 (10:99646738 G>A), RS1000654253 (10:99648454 T>C), RS1000714011 (10:99653437 C>T), RS1000719162 (10:99641337 T>C), RS1000745914 (10:99656547 T>C)

Disease associations

OMIM: gene MIM:609767 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001438_10	Crohn’s disease	5.000000e-07
GCST001800_9	β2-Glycoprotein I (β2-GPI) plasma levels	2.000000e-06
GCST002411_7	Colorectal cancer	5.000000e-11
GCST002919_10	Colorectal cancer	8.000000e-07
GCST003017_4	Colorectal cancer	8.000000e-07
GCST003017_9	Colorectal cancer	4.000000e-08
GCST006479_115	Diverticular disease	1.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004555	glycoprotein measurement
EFO:0009959	diverticular disease

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC25 mitochondrial iron transporters subfamily

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects cotreatment, decreases reaction, increases expression, decreases methylation	6
bisphenol A	increases methylation, decreases expression	2
Arsenic Trioxide	decreases expression, increases expression	2
Acetaminophen	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
1,6-hexamethylene diisocyanate	increases methylation	1
afimoxifene	decreases reaction, increases expression	1
sodium arsenite	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases reaction, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	increases abundance, increases methylation	1
Ethanol	affects cotreatment, decreases reaction, increases expression	1
Vehicle Emissions	increases abundance, increases methylation	1
Environmental Pollutants	affects expression	1
Estrogens	decreases reaction, increases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Nickel	increases expression	1
Nitrogen Dioxide	increases abundance, increases methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tunicamycin	increases expression	1
Urethane	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1HL	Abcam A-549 SLC25A28 KO 2	Cancer cell line	Male
CVCL_B2Q4	Abcam A-549 SLC25A28 KO 1	Cancer cell line	Male
CVCL_D4DY	HEK-SLC25A28-KO-c1	Transformed cell line	Female
CVCL_D4DZ	HEK-SLC25A28-KO-c10	Transformed cell line	Female
CVCL_D4JP	HCT116-SLC25A28-KO-c3	Cancer cell line	Male
CVCL_D4JQ	HCT116-SLC25A28-KO-c9	Cancer cell line	Male
CVCL_TM28	HAP1 SLC25A28 (-) 1	Cancer cell line	Male
CVCL_XT04	HAP1 SLC25A28 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.