SLC25A5

Summary

SLC25A5 (solute carrier family 25 member 5, HGNC:10991) is a protein-coding gene on chromosome Xq24, encoding ADP/ATP translocase 2 (P05141). ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell. It is a selective cancer dependency (DepMap: 25.1% of cell lines).

This gene is a member of the mitochondrial carrier subfamily of solute carrier protein genes. The product of this gene functions as a gated pore that translocates ADP from the cytoplasm into the mitochondrial matrix and ATP from the mitochondrial matrix into the cytoplasm. The protein forms a homodimer embedded in the inner mitochondria membrane. Suppressed expression of this gene has been shown to induce apoptosis and inhibit tumor growth. The human genome contains several non-transcribed pseudogenes of this gene.

Source: NCBI Gene 292 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability (Limited, GenCC)
• Clinical variants (ClinVar): 67 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 25.1% of screened cell lines
• MANE Select transcript: NM_001152

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10991
Approved symbol	SLC25A5
Name	solute carrier family 25 member 5
Location	Xq24
Locus type	gene with protein product
Status	Approved
Aliases	T2, 2F1, T3
Ensembl gene	ENSG00000005022
Ensembl biotype	protein_coding
OMIM	300150
Entrez	292

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000317881, ENST00000460013, ENST00000463551, ENST00000475354, ENST00000879015, ENST00000879016, ENST00000879017, ENST00000879018, ENST00000915388, ENST00000941018

RefSeq mRNA: 1 — MANE Select: NM_001152 NM_001152

CCDS: CCDS14578

Canonical transcript exons

ENST00000317881 — 4 exons

Exon	Start	End
ENSE00001257617	119470901	119471396
ENSE00001257624	119468444	119468626
ENSE00003662030	119469661	119470147
ENSE00003667517	119470373	119470513

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 278.8216 / max 1456.0924, expressed in 1828 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197394	216.3359	1827
197393	61.7173	1824
197395	0.7684	445

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	99.87	gold quality
jejunal mucosa	UBERON:0000399	99.86	gold quality
ileal mucosa	UBERON:0000331	99.80	gold quality
pharyngeal mucosa	UBERON:0000355	99.73	gold quality
duodenum	UBERON:0002114	99.72	gold quality
thymus	UBERON:0002370	99.72	gold quality
mucosa of transverse colon	UBERON:0004991	99.72	gold quality
colonic mucosa	UBERON:0000317	99.70	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.68	gold quality
mammalian vulva	UBERON:0000997	99.65	gold quality
penis	UBERON:0000989	99.64	gold quality
epithelium of nasopharynx	UBERON:0001951	99.63	gold quality
pylorus	UBERON:0001166	99.62	gold quality
nipple	UBERON:0002030	99.61	gold quality
pons	UBERON:0000988	99.59	gold quality
upper leg skin	UBERON:0004262	99.56	gold quality
adult mammalian kidney	UBERON:0000082	99.51	gold quality
rectum	UBERON:0001052	99.50	gold quality
cardia of stomach	UBERON:0001162	99.47	gold quality
body of pancreas	UBERON:0001150	99.46	gold quality
oral cavity	UBERON:0000167	99.43	gold quality
transverse colon	UBERON:0001157	99.42	gold quality
superior surface of tongue	UBERON:0007371	99.35	gold quality
trachea	UBERON:0003126	99.34	gold quality
adult organism	UBERON:0007023	99.34	gold quality
cerebellar vermis	UBERON:0004720	99.32	gold quality
body of stomach	UBERON:0001161	99.30	gold quality
tongue	UBERON:0001723	99.30	gold quality
tongue squamous epithelium	UBERON:0006919	99.30	gold quality
body of tongue	UBERON:0011876	99.30	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	115.99
E-HCAD-4	yes	91.53
E-MTAB-8410	yes	44.45
E-CURD-46	yes	24.40
E-CURD-122	yes	23.85
E-MTAB-9067	yes	20.19
E-MTAB-10042	yes	17.65
E-CURD-112	yes	10.27
E-MTAB-10553	yes	8.80
E-CURD-88	yes	5.74
E-CURD-79	no	1709.45
E-GEOD-76312	no	1647.78
E-MTAB-10432	no	691.31
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HES1, KMT2A, MBD2, MYC, MYOG, NFIA, NFKB, NRF1, PAX8, POU1F1, SALL3, SP1, STAT3, TFAM, THRB, TP53, ZNF699

miRNA regulators (miRDB)

58 targeting SLC25A5, 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-6798-5P	100.00	65.77	699
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-190A-5P	99.54	71.45	933
HSA-MIR-190B-5P	99.54	71.40	925
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-135A-5P	99.36	71.85	1601
HSA-MIR-135B-5P	99.36	71.63	1613
HSA-MIR-7158-5P	99.25	67.95	796
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-361-5P	98.95	70.16	1340

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 25.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 24)

• ANT2 is able to restore growth on a nonfermentable carbon source of a yeast mutant strain lacking its three endogenous ANC. (PMID:12450408)
• enhanced binding of NF1 is a key step in the growth arrest repression of ANT2 transcription. (PMID:12777383)
• expression under hypoxic conditions alters cell cycle in cancer cells (PMID:15486956)
• Growth-dependent repression of human adenine nucleotide translocator-2 (ANT2) transcription. (PMID:18215124)
• ANT2-specific RNA interference approach to inhibit ANT2 expression resulted in breast cancer cell growth arrest (PMID:18267033)
• ANT2 shRNA treatment sensitized MCF7, T47 D, and BT474 cells to TRAIL-induced apoptosis by up-regulating the expression of TRAIL death receptors 4 and 5 (DR4 and DR5) and down-regulating the TRAIL decoy receptor 2 (DcR2). (PMID:20875141)
• ANT2 is not pro-apoptotic and may therefore contribute to carcinogenesis. (PMID:20950584)
• In the context of ovarian cancer, the interaction between CKIepsilon and ANT2 mediates pathogenic signalling that is distinct from the canonical Wnt/beta-catenin pathway and is essential for cell proliferation and is clinically associated with poor survival. (PMID:22707389)
• The mammalian proteins MMS19, MIP18, and ANT2 are involved in cytoplasmic iron-sulfur cluster protein assembly. (PMID:23150669)
• ANT2 suppression by shRNA may be able to exert anticancer effects in HCC further by restoring SOCS1 expression (PMID:23242177)
• Compares and contrasts all the known human SLC25A* genes and includes functional information. (PMID:23266187)
• miR-636 might function as a tumor suppressor miRNA affecting hepatocellular carcinoma (HCC) tumorigenesis via downregulation of Ras, and that ANT2 suppression by shRNA could exert an anticancer effect by restoring miR-636 expression in HCC. (PMID:23306701)
• Apigenin upregulates DR5 and enhances TRAIL induced apoptosis by binding and inhibiting ANT2. (PMID:23431365)
• SLC25A5 is involved in memory formation or establishment, which could add mitochondrial processes to the wide array of pathways that regulate normal cognitive functions. (PMID:23783460)
• Sirt4 regulates ATP levels via ANT2 and a feedback loop involving AMPK. (PMID:24296486)
• TGF-beta-mediated suppression of ANT2 through NF1/Smad4 complexes contributes to oxidative stress and DNA damage during induction of cellular senescence. (PMID:25220407)
• IFNgamma induces oxidative stress, DNA damage and tumor cell senescence via TGFbeta/SMAD signaling-dependent induction of Nox4 and suppression of ANT2 (PMID:25982278)
• cancer cells require both hANT2 and hANT3, depending on their proliferation status: hANT2 when proliferation rates are high, and hANT3 when proliferation slows. (PMID:26842067)
• Findings suggest that ANT2 overexpression contributes to EGFR-TKI resistance in non-small cell lung cancer. (PMID:26883272)
• ANT2 shRNA downregulates miR-19a and miR-96 through the PI3K/Akt pathway and suppresses tumor growth in hepatocellular carcinoma cells. (PMID:27012708)
• Study found that ANT2 was upregulated in sorafenibresistant hepatocellular carcinoma Huh7 cell line and its overexpression promoted sorafenib resistance. (PMID:28350139)
• ANT2 can be used as a marker of dedifferentiated pathology and aggressiveness of cancer. (PMID:30225759)
• Differential Expression of ADP/ATP Carriers as a Biomarker of Metabolic Remodeling and Survival in Kidney Cancers. (PMID:33396658)
• ANT2 drives proinflammatory macrophage activation in obesity. (PMID:34676827)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc25a5	ENSDARG00000092553
mus_musculus	Slc25a5	ENSMUSG00000016319
rattus_norvegicus	Slc25a5	ENSRNOG00000039980
rattus_norvegicus	Slc25a5-ps11	ENSRNOG00000042387
rattus_norvegicus		ENSRNOG00000063076

Paralogs (49): SLC25A13 (ENSG00000004864), 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), SLC25A28 (ENSG00000155287), SLC25A44 (ENSG00000160785), SLC25A45 (ENSG00000162241), SLC25A34 (ENSG00000162461), SLC25A32 (ENSG00000164933), SLC25A6 (ENSG00000169100), SLC25A33 (ENSG00000171612), SLC25A30 (ENSG00000174032), UCP3 (ENSG00000175564), UCP2 (ENSG00000175567)

Protein

Protein identifiers

ADP/ATP translocase 2 — P05141 (reviewed: P05141)

Alternative names: ADP,ATP carrier protein 2, ADP,ATP carrier protein, fibroblast isoform, Adenine nucleotide translocator 2, Solute carrier family 25 member 5

All UniProt accessions (1): P05141

UniProt curated annotations — full annotation on UniProt →

Function. ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell. Cycles between the cytoplasmic-open state (c-state) and the matrix-open state (m-state): operates by the alternating access mechanism with a single substrate-binding site intermittently exposed to either the cytosolic (c-state) or matrix (m-state) side of the inner mitochondrial membrane. In addition to its ADP:ATP antiporter activity, also involved in mitochondrial uncoupling and mitochondrial permeability transition pore (mPTP) activity. Plays a role in mitochondrial uncoupling by acting as a proton transporter: proton transport uncouples the proton flows via the electron transport chain and ATP synthase to reduce the efficiency of ATP production and cause mitochondrial thermogenesis. Proton transporter activity is inhibited by ADP:ATP antiporter activity, suggesting that SLC25A5/ANT2 acts as a master regulator of mitochondrial energy output by maintaining a delicate balance between ATP production (ADP:ATP antiporter activity) and thermogenesis (proton transporter activity). Proton transporter activity requires free fatty acids as cofactor, but does not transport it. Probably mediates mitochondrial uncoupling in tissues that do not express UCP1. Also plays a key role in mPTP opening, a non-specific pore that enables free passage of the mitochondrial membranes to solutes of up to 1.5 kDa, and which contributes to cell death. It is however unclear if SLC25A5/ANT2 constitutes a pore-forming component of mPTP or regulates it. Acts as a regulator of mitophagy independently of ADP:ATP antiporter activity: promotes mitophagy via interaction with TIMM44, leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1. As part of the mitotic spindle-associated MMXD complex it may play a role in chromosome segregation.

Subunit / interactions. Monomer. Component of the MMXD complex, which includes CIAO1, ERCC2, CIAO2B, MMS19 and SLC25A5/ANT2. Interacts with AK4. Interacts with ARHGAP11B, thereby inhibiting the mitochondrial permeability transition pore (mPTP). Interacts with TIMM44; leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1. (Microbial infection) Interacts with HIV-1 Vpr.

Subcellular location. Mitochondrion inner membrane. Membrane.

Tissue specificity. Expressed in erythrocytes (at protein level).

Post-translational modifications. Trimethylated by ANTKMT at Lys-52.

Activity regulation. The matrix-open state (m-state) is inhibited by the membrane-permeable bongkrekic acid (BKA). The cytoplasmic-open state (c-state) is inhibited by the membrane-impermeable toxic inhibitor carboxyatractyloside (CATR). Proton transporter activity is inhibited by ADP:ATP antiporter activity.

Domain organisation. The transmembrane helices are not perpendicular to the plane of the membrane, but cross the membrane at an angle. Odd-numbered transmembrane helices exhibit a sharp kink, due to the presence of a conserved proline residue.

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

RefSeq proteins (1): NP_001143* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002067	MCP	Family
IPR002113	ADT_euk_type	Family
IPR018108	MCP_transmembrane	Repeat
IPR023395	MCP_dom_sf	Homologous_superfamily

Pfam: PF00153

Catalyzed reactions (Rhea), 2 shown:

• H(+)(in) = H(+)(out) (RHEA:34979)
• ADP(in) + ATP(out) = ADP(out) + ATP(in) (RHEA:34999)

UniProt features (49 total): modified residue 20, topological domain 7, transmembrane region 6, sequence conflict 4, repeat 3, binding site 3, chain 2, initiator methionine 1, region of interest 1, short sequence motif 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05141-F1	91.76	0.74

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (3): 80; 92; 235

Post-translational modifications (20): 1, 2, 7, 23, 43, 52, 52, 52, 92, 96, 105, 105, 147, 147, 147, 147, 163, 166, 268, 268

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-180897	Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization
R-HSA-83936	Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-162906	HIV Infection
R-HSA-162909	Host Interactions of HIV factors
R-HSA-1643685	Disease
R-HSA-176033	Interactions of Vpr with host cellular proteins
R-HSA-382551	Transport of small molecules
R-HSA-392499	Metabolism of proteins
R-HSA-425397	Transport of vitamins, nucleosides, and related molecules
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5663205	Infectious disease
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 333 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, AAGCAAT_MIR137, HORIUCHI_WTAP_TARGETS_DN, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INTERACTIONS_OF_VPR_WITH_HOST_CELLULAR_PROTEINS, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_MYELOID_CELL_HOMEOSTASIS, SWEET_KRAS_ONCOGENIC_SIGNATURE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_B_CELL_ACTIVATION, MODULE_151, GCANCTGNY_MYOD_Q6, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, AAGCCAT_MIR135A_MIR135B, GOBP_ERYTHROCYTE_HOMEOSTASIS

GO Biological Process (15): chromosome segregation (GO:0007059), positive regulation of cell population proliferation (GO:0008284), B cell differentiation (GO:0030183), erythrocyte differentiation (GO:0030218), regulation of mitochondrial membrane permeability (GO:0046902), adenine nucleotide transport (GO:0051503), mitochondrial ADP transmembrane transport (GO:0140021), negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway (GO:1901029), positive regulation of mitophagy (GO:1901526), mitochondrial ATP transmembrane transport (GO:1990544), cellular response to leukemia inhibitory factor (GO:1990830), adaptive thermogenesis (GO:1990845), adenine transport (GO:0015853), transmembrane transport (GO:0055085), proton transmembrane transport (GO:1902600)

GO Molecular Function (9): adenine nucleotide transmembrane transporter activity (GO:0000295), RNA binding (GO:0003723), ATP:ADP antiporter activity (GO:0005471), proton transmembrane transporter activity (GO:0015078), adenine transmembrane transporter activity (GO:0015207), oxidative phosphorylation uncoupler activity (GO:0017077), ubiquitin protein ligase binding (GO:0031625), protein binding (GO:0005515), antiporter activity (GO:0015297)

GO Cellular Component (8): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial permeability transition pore complex (GO:0005757), plasma membrane (GO:0005886), membrane (GO:0016020), mitochondrial nucleoid (GO:0042645), MMXD complex (GO:0071817)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Interactions of Vpr with host cellular proteins	1
Transport of vitamins, nucleosides, and related molecules	1
Metabolism of proteins	1
Viral Infection Pathways	1
HIV Infection	1
Host Interactions of HIV factors	1
SLC-mediated transmembrane transport	1
Transport of small molecules	1
Disease	1
Infectious disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
purine-containing compound transmembrane transport	2
nucleotide transmembrane transport	2
proton transmembrane transport	2
intracellular membrane-bounded organelle	2
cell cycle process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
lymphocyte differentiation	1
B cell activation	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
regulation of membrane permeability	1
purine nucleotide transport	1
ADP transport	1
negative regulation of organelle organization	1
negative regulation of mitochondrial membrane permeability	1
mitochondrial outer membrane permeabilization	1
regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway	1
negative regulation of apoptotic signaling pathway	1
mitophagy	1
positive regulation of macroautophagy	1
regulation of mitophagy	1
positive regulation of autophagy of mitochondrion	1
ATP transport	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
temperature homeostasis	1
purine nucleobase transport	1
transport	1
cellular process	1
monoatomic cation transmembrane transport	1
purine nucleotide transmembrane transporter activity	1
adenine nucleotide transport	1
nucleic acid binding	1
ATP transmembrane transporter activity	1
ADP transmembrane transporter activity	1
antiporter activity	1
monoatomic cation transmembrane transporter activity	1
purine nucleobase transmembrane transporter activity	1

Protein interactions and networks

STRING

2903 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC25A5	MMS19	Q96T76	948
SLC25A5	CIAO2B	Q9Y3D0	947
SLC25A5	CIAO1	O76071	936
SLC25A5	VDAC1	P21796	795
SLC25A5	SIRT4	Q9Y6E7	790
SLC25A5	MTCH1	Q9NZJ7	717
SLC25A5	VDAC2	P45880	699
SLC25A5	CYCS	P00001	696
SLC25A5	SLC25A3	Q00325	693
SLC25A5	MTCH2	Q9Y6C9	622
SLC25A5	PHB1	P35232	569
SLC25A5	SLC35F6	Q8N357	567
SLC25A5	TIMM13	P62206	514
SLC25A5	HSPA9	P30036	511
SLC25A5	PC	P11498	498

IntAct

351 interactions, top by confidence:

A	B	Type	Score
PRKAA1	PRKAB2	psi-mi:“MI:0914”(association)	0.950
MAP3K14	CHUK	psi-mi:“MI:0914”(association)	0.950
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
RCC1L	NME6	psi-mi:“MI:0914”(association)	0.720
IFT88	IFT56	psi-mi:“MI:0914”(association)	0.640
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
TUBB3	POTEF	psi-mi:“MI:0914”(association)	0.530
CCNJL	PIK3C2A	psi-mi:“MI:0914”(association)	0.530
DKK3	NME4	psi-mi:“MI:0914”(association)	0.530
COQ2	SLC25A5	psi-mi:“MI:0914”(association)	0.530
APOOL	MTX2	psi-mi:“MI:0914”(association)	0.530
GRB2	ARHGEF35	psi-mi:“MI:0914”(association)	0.530
PRKCZ	IPO5	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
TUBA1A	TUBAL3	psi-mi:“MI:0914”(association)	0.420
ARHGAP28	SLC25A5	psi-mi:“MI:0915”(physical association)	0.400
BDP1	SLC25A5	psi-mi:“MI:0915”(physical association)	0.400
PMFBP1	SLC25A5	psi-mi:“MI:0915”(physical association)	0.400
SLC25A5		psi-mi:“MI:0915”(physical association)	0.370
OTUB1		psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350

BioGRID (562): SLC25A5 (Affinity Capture-MS), SLC25A5 (Affinity Capture-MS), SLC25A5 (Affinity Capture-MS), SLC25A5 (Affinity Capture-MS), SLC25A5 (Affinity Capture-MS), SLC25A5 (Affinity Capture-MS), SLC25A5 (Affinity Capture-MS), SLC25A5 (Affinity Capture-MS), ATP6V0D1 (Co-fractionation), HNRNPU (Co-fractionation), NDUFS4 (Co-fractionation), PMM2 (Co-fractionation), SLC25A20 (Co-fractionation), SLC25A24 (Co-fractionation), SLC25A4 (Co-fractionation)

ESM2 similar proteins: A6QR09, F1R4U0, F1RFX9, O43772, O46373, O77792, O95258, O97562, O97649, P02722, P05141, P12235, P12236, P22292, P32007, P32089, P48962, P51881, P53007, P55851, P70406, P79110, P97700, Q000K2, Q02978, Q05962, Q08DK4, Q09073, Q3SZI5, Q5PQM9, Q5R5A1, Q5R5A8, Q5SVS4, Q5U680, Q5XGI1, Q6GQ22, Q6QRN9, Q70HW3, Q8HXE3, Q8HXY2

Diamond homologs: A0A1D6N272, A1DI57, A2A3V2, A2ASZ8, A2CEQ0, A5PJZ1, B0G159, B4F8I5, B4FIJ0, B8ZHC9, F1LX07, F4HW79, F4JU70, K7VYZ9, O04619, O18757, O65023, O75746, O81845, O94502, O97649, P04710, P05141, P0C546, P0CI40, P12235, P12857, P16260, P16261, P25083, P29518, P31167, P31691, P40941, P48962, P55916, Q01888, Q05AQ3, Q0II44, Q0P483

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PAK6	“up-regulates quantity”	SLC25A5	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 193 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	5	20.3×	5e-04
Transport of connexons to the plasma membrane	5	20.3×	5e-04
Activation of AMPK downstream of NMDARs	7	19.9×	4e-05
Gap junction trafficking and regulation	5	17.8×	5e-04
Gap junction trafficking	5	17.8×	5e-04
Nuclear Envelope (NE) Reassembly	6	13.1×	5e-04
Aggrephagy	7	13.0×	3e-04
RHO GTPases activate IQGAPs	5	12.9×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	6	12.7×	5e-03
G1/S transition of mitotic cell cycle	10	11.8×	2e-05
mitochondrion organization	8	7.1×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	10
Likely benign	12
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

461 predictions. Top by Δscore:

Variant	Effect	Δscore
X:119468623:GCAG:G	donor_gain	1.0000
X:119468624:CAGG:C	donor_loss	1.0000
X:119468626:GGTA:G	donor_loss	1.0000
X:119468627:GTA:G	donor_loss	1.0000
X:119470365:A:AG	acceptor_gain	1.0000
X:119470366:T:G	acceptor_gain	1.0000
X:119470368:CCCA:C	acceptor_loss	1.0000
X:119470369:CCA:C	acceptor_loss	1.0000
X:119470370:CA:C	acceptor_loss	1.0000
X:119470371:A:AG	acceptor_gain	1.0000
X:119470371:A:T	acceptor_loss	1.0000
X:119470371:AG:A	acceptor_gain	1.0000
X:119470372:G:GA	acceptor_gain	1.0000
X:119470372:GG:G	acceptor_gain	1.0000
X:119470372:GGA:G	acceptor_gain	1.0000
X:119470372:GGAA:G	acceptor_gain	1.0000
X:119470372:GGAAT:G	acceptor_gain	1.0000
X:119470509:AGGAA:A	donor_gain	1.0000
X:119470510:GGAA:G	donor_gain	1.0000
X:119470510:GGAAG:G	donor_gain	1.0000
X:119470511:G:T	donor_gain	1.0000
X:119470511:GAA:G	donor_gain	1.0000
X:119470511:GAAG:G	donor_gain	1.0000
X:119470512:A:T	donor_gain	1.0000
X:119470512:AA:A	donor_gain	1.0000
X:119470513:AG:A	donor_loss	1.0000
X:119470514:G:GG	donor_gain	1.0000
X:119470514:GTAAG:G	donor_loss	1.0000
X:119470515:TAA:T	donor_loss	1.0000
X:119470896:T:TA	acceptor_gain	1.0000

AlphaMissense

1939 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:119468561:G:A	G16R	1.000
X:119468561:G:C	G16R	1.000
X:119468562:G:A	G16E	1.000
X:119468598:C:A	P28H	1.000
X:119468616:T:C	L34P	1.000
X:119469720:C:G	C57W	1.000
X:119469766:G:C	G73R	1.000
X:119469767:G:A	G73D	1.000
X:119469767:G:T	G73V	1.000
X:119469771:C:A	N74K	1.000
X:119469771:C:G	N74K	1.000
X:119469952:G:C	D135H	1.000
X:119469953:A:T	D135V	1.000
X:119469971:T:C	L141P	1.000
X:119470009:T:C	F154L	1.000
X:119470011:C:A	F154L	1.000
X:119470011:C:G	F154L	1.000
X:119470029:C:G	C160W	1.000
X:119470075:G:C	G176R	1.000
X:119470123:T:C	F192L	1.000
X:119470125:C:A	F192L	1.000
X:119470125:C:G	F192L	1.000
X:119470480:C:A	R236S	1.000
X:119470932:C:G	C257W	1.000
X:119470978:G:C	G273R	1.000
X:119470978:G:T	G273C	1.000
X:119468558:G:C	G15R	0.999
X:119468559:G:A	G15D	0.999
X:119468568:C:A	A18D	0.999
X:119468571:C:A	A19E	0.999

dbSNP variants (sampled 300 via entrez): RS1001107452 (X:119471471 C>T), RS1001118558 (X:119469498 C>T), RS1001485333 (X:119469065 G>C), RS1002129595 (X:119467804 A>T), RS1004396047 (X:119471605 A>G), RS1004962944 (X:119471872 C>T), RS1005867797 (X:119468988 C>T), RS1005920056 (X:119468502 C>T), RS1008882262 (X:119469046 G>A,T), RS1009820292 (X:119469091 C>G), RS1010427974 (X:119468374 G>A,C), RS1010823255 (X:119471740 T>A), RS1012226983 (X:119471536 A>G), RS1012921330 (X:119471841 C>T), RS1013510074 (X:119468469 G>T)

Disease associations

OMIM: gene MIM:300150 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability	Limited	X-linked

Mondo (1): intellectual disability (MONDO:0001071)

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3709670 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 3,933 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL1232461	MOLIBRESIB	2	1,538

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — Mitochondrial nucleotide transporter subfamily

ChEMBL bioactivities

6 potent at pChembl≥5 of 8 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.73	Kd	186.1	nM	CHEMBL5653589
6.73	ED50	186.1	nM	CHEMBL5653589
6.39	IC50	410	nM	MOLIBRESIB
6.35	Kd	451	nM	GILTERITINIB
5.59	Kd	2543	nM	CHEMBL3752910
5.59	ED50	2543	nM	CHEMBL3752910

PubChem BioAssay actives

4 with measured affinity, of 252 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149411: Binding affinity to human SLC25A5 incubated for 45 mins by Kinobead based pull down assay	kd	0.1861	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178876: Inhibition of SLC25A5 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.4100	uM
Gilteritinib	1425169: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.4510	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149411: Binding affinity to human SLC25A5 incubated for 45 mins by Kinobead based pull down assay	kd	2.5431	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases expression, decreases expression	4
bisphenol A	affects expression, decreases expression, increases expression	3
CD 437	decreases activity, decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Doxorubicin	affects expression, increases expression	2
Valproic Acid	affects cotreatment, increases expression, increases methylation	2
dehydroabietylamine	increases activity	1
FR900359	increases phosphorylation	1
carboxyatractyloside	decreases activity	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
terbufos	increases methylation	1
arsenite	increases reaction, affects binding, decreases reaction	1
closantel	decreases activity	1
oxophenylarsine	decreases activity	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
azoxystrobin	increases expression	1
chloropicrin	affects expression	1
corosolic acid	decreases expression	1
K 7174	increases expression	1
pyrimidifen	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
pyrachlostrobin	increases expression	1
picoxystrobin	increases expression	1
Acetaminophen	increases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment	1
Atractyloside	decreases activity	1

ChEMBL screening assays

12 unique, capped per target: 12 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3882222	Binding	Inhibition of ANT2 in human HeLa cells assessed as growth inhibition at 50 uM incubated for 5 days by crystal violet staining based assay	ANT2 inhibitor compounds and methods of use thereof

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2FS	Abcam HeLa SLC25A5 KO	Cancer cell line	Female
CVCL_D4KF	HCT116-SLC25A5-KO-c10	Cancer cell line	Male
CVCL_D4KG	HCT116-SLC25A5-KO-c2	Cancer cell line	Male
CVCL_D8V8	Ubigene HCT 116 SLC25A5 KO	Cancer cell line	Male
CVCL_D9RU	Ubigene HEK293 SLC25A5 KO	Transformed cell line	Female
CVCL_E0WV	Ubigene KYSE-150 SLC25A5 KO	Cancer cell line	Female
CVCL_TM55	HAP1 SLC25A5 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders