CISD3

Summary

CISD3 (CDGSH iron sulfur domain 3, HGNC:27578) is a protein-coding gene on chromosome 17q12, encoding CDGSH iron-sulfur domain-containing protein 3, mitochondrial (P0C7P0). Can transfer its iron-sulfur clusters to the apoferrodoxins FDX1 and FDX2.

CISD3 is a member of the CDGSH domain-containing family, which may play a role in regulating electron transport and oxidative phosphorylation (Wiley et al., 2007 [PubMed 17376863]).

Source: NCBI Gene 284106 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 130 total
• MANE Select transcript: NM_001136498

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27578
Approved symbol	CISD3
Name	CDGSH iron sulfur domain 3
Location	17q12
Locus type	gene with protein product
Status	Approved
Aliases	Miner2, MiNT
Ensembl gene	ENSG00000277972
Ensembl biotype	protein_coding
OMIM	611933
Entrez	284106

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 retained_intron

ENST00000613478, ENST00000616128, ENST00000619858, ENST00000894448, ENST00000894449, ENST00000894450, ENST00000939173

RefSeq mRNA: 1 — MANE Select: NM_001136498 NM_001136498

CCDS: CCDS45662

Canonical transcript exons

ENST00000613478 — 4 exons

Exon	Start	End
ENSE00003732535	38731320	38731439
ENSE00003736893	38733276	38735605
ENSE00003740030	38730760	38730795
ENSE00003749580	38730341	38730406

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 97.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.2557 / max 82.9579, expressed in 1797 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160516	11.0184	1778
160515	1.2373	882

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	97.74	gold quality
apex of heart	UBERON:0002098	97.11	gold quality
right lobe of liver	UBERON:0001114	97.06	gold quality
liver	UBERON:0002107	95.80	gold quality
body of pancreas	UBERON:0001150	95.49	gold quality
duodenum	UBERON:0002114	95.30	gold quality
heart left ventricle	UBERON:0002084	95.21	gold quality
transverse colon	UBERON:0001157	94.28	gold quality
right adrenal gland	UBERON:0001233	93.90	gold quality
adult mammalian kidney	UBERON:0000082	93.80	gold quality
left adrenal gland cortex	UBERON:0035825	93.80	gold quality
left adrenal gland	UBERON:0001234	93.65	gold quality
right atrium auricular region	UBERON:0006631	93.52	gold quality
heart	UBERON:0000948	93.49	gold quality
body of stomach	UBERON:0001161	93.43	gold quality
right adrenal gland cortex	UBERON:0035827	93.30	gold quality
prefrontal cortex	UBERON:0000451	92.94	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.75	gold quality
small intestine	UBERON:0002108	92.62	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.62	gold quality
colon	UBERON:0001155	92.58	gold quality
fundus of stomach	UBERON:0001160	92.42	gold quality
granulocyte	CL:0000094	92.31	gold quality
left coronary artery	UBERON:0001626	92.20	gold quality
intestine	UBERON:0000160	92.00	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.91	gold quality
pancreas	UBERON:0001264	91.80	gold quality
gastrocnemius	UBERON:0001388	91.74	gold quality
adrenal gland	UBERON:0002369	91.64	gold quality
muscle of leg	UBERON:0001383	91.54	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	45.73
E-ANND-3	yes	17.65
E-CURD-112	yes	13.21
E-MTAB-9543	yes	10.01
E-HCAD-13	yes	7.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

95 targeting CISD3, 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-6867-5P	100.00	82.21	3464
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-1296-3P	99.72	64.04	636
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084

Literature-anchored findings (GeneRIF, showing 3)

• Data indicate that mitochondrial inner NEET protein (MiNT)functions within the mitochondria to regulate levels of toxic iron and reactive oxygen species (ROS). (PMID:29259115)
• CISD3 inhibition drives cystine-deprivation induced ferroptosis. (PMID:34497268)
• Biochemical and cellular characterization of the CISD3 protein: Molecular bases of cluster release and destabilizing effects of nitric oxide. (PMID:38354784)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cisd3	ENSMUSG00000078695
rattus_norvegicus	Cisd3	ENSRNOG00000036894
drosophila_melanogaster	CG3420	FBGN0033100
caenorhabditis_elegans		WBGENE00022053

Paralogs (2): CISD1 (ENSG00000122873), CISD2 (ENSG00000145354)

Protein

Protein identifiers

CDGSH iron-sulfur domain-containing protein 3, mitochondrial — P0C7P0 (reviewed: P0C7P0)

Alternative names: MitoNEET-related protein 2, Mitochondrial inner NEET protein

All UniProt accessions (1): P0C7P0

UniProt curated annotations — full annotation on UniProt →

Function. Can transfer its iron-sulfur clusters to the apoferrodoxins FDX1 and FDX2. Contributes to mitochondrial iron homeostasis and in maintaining normal levels of free iron and reactive oxygen species, and thereby contributes to normal mitochondrial function.

Subunit / interactions. Monomer.

Subcellular location. Mitochondrion.

Cofactor. Binds 2 [2Fe-2S] clusters per subunit.

Similarity. Belongs to the CISD protein family.

RefSeq proteins (1): NP_001129970* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018967	FeS-contain_CDGSH-typ	Domain
IPR042216	MitoNEET_CISD	Homologous_superfamily
IPR052950	CISD	Family

Pfam: PF09360

UniProt features (24 total): binding site 8, strand 6, modified residue 3, helix 3, mutagenesis site 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6AVJ	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0C7P0-F1	87.67	0.72

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 (8): 60; 62; 71; 75; 98; 100; 109; 113

Post-translational modifications (3): 55, 55, 86

Mutagenesis-validated functional residues (2):

Position	Phenotype
75	increases iron-sulfur cluster stability; when associated with c-113.
113	increases iron-sulfur cluster stability; when associated with c-75.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 95 (showing top): GOBP_PROTEIN_MATURATION, GOMF_METAL_CLUSTER_BINDING, GOMF_2_IRON_2_SULFUR_CLUSTER_BINDING, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_DN, VANLOO_SP3_TARGETS_DN, ATF6_TARGET_GENES, BARX1_TARGET_GENES, CREB3L4_TARGET_GENES, DLX6_TARGET_GENES, FOXD2_TARGET_GENES, ID1_TARGET_GENES, ID2_TARGET_GENES, NAB2_TARGET_GENES, SNRNP70_TARGET_GENES, UBN1_TARGET_GENES

GO Biological Process (1): protein maturation (GO:0051604)

GO Molecular Function (3): metal ion binding (GO:0046872), 2 iron, 2 sulfur cluster binding (GO:0051537), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (3): mitochondrion (GO:0005739), cytoplasm (GO:0005737), intracellular membrane-bounded organelle (GO:0043231)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
gene expression	1
protein metabolic process	1
cation binding	1
iron-sulfur cluster binding	1
metal cluster binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
membrane-bounded organelle	1
intracellular organelle	1

Protein interactions and networks

STRING

808 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CISD3	CISD1	Q9NZ45	991
CISD3	CISD2	Q8N5K1	962
CISD3	FDX1	P10109	540
CISD3	RPL28	P46779	454
CISD3	CIMAP1C	Q8IXM7	453
CISD3	MNT	Q99583	447
CISD3	HSPB3	Q12988	437
CISD3	CFTR	P13569	424
CISD3	RPL27A	P46776	424
CISD3	CPEB2	Q7Z5Q1	420
CISD3	CIAPIN1	Q6FI81	418
CISD3	ACO1	P21399	404
CISD3	WFS1	O76024	386
CISD3	ATXN7L3B	Q96GX2	384
CISD3	DNAJC30	Q96LL9	380

IntAct

24 interactions, top by confidence:

A	B	Type	Score
CHCHD4	SSNA1	psi-mi:“MI:0914”(association)	0.640
LRFN4	RIMOC1	psi-mi:“MI:0914”(association)	0.530
CACNG5	ZNF316	psi-mi:“MI:0914”(association)	0.530
HAVCR2	TCAF2	psi-mi:“MI:0914”(association)	0.530
ADAM33	LRP5	psi-mi:“MI:0914”(association)	0.530
	PLOD2	psi-mi:“MI:0914”(association)	0.530
NCAPD3	SMC2	psi-mi:“MI:0914”(association)	0.350
SMOC1	NME2	psi-mi:“MI:0914”(association)	0.350
CISD3	POLRMT	psi-mi:“MI:0914”(association)	0.350
CISD3	COQ9	psi-mi:“MI:0914”(association)	0.350
CISD3	TIMM44	psi-mi:“MI:0914”(association)	0.350
IGF1R	HAX1	psi-mi:“MI:0914”(association)	0.350
S100B	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
ADAM33	ADAM10	psi-mi:“MI:0914”(association)	0.350
ABCA6	STX6	psi-mi:“MI:0914”(association)	0.350
SLC30A1	PSMD11	psi-mi:“MI:0914”(association)	0.350
SLC31A1	DENND11	psi-mi:“MI:0914”(association)	0.350
STAT3	IDH3B	psi-mi:“MI:0914”(association)	0.350

BioGRID (100): CISD3 (Affinity Capture-MS), CISD3 (Affinity Capture-MS), MIPEP (Affinity Capture-MS), ERAL1 (Affinity Capture-MS), AFG3L2 (Affinity Capture-MS), CLPX (Affinity Capture-MS), GRSF1 (Affinity Capture-MS), SCO2 (Affinity Capture-MS), CLPB (Affinity Capture-MS), PMPCA (Affinity Capture-MS), PMPCB (Affinity Capture-MS), TRMT10C (Affinity Capture-MS), POLRMT (Affinity Capture-MS), CHCHD2 (Affinity Capture-MS), STOML2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L1SUL6, A4QJJ7, A4QK16, A6H5F6, A6MM34, A6NH52, A6NMK7, A7M939, A8SEA1, A8W3M5, B0Z4S1, B0Z505, B0Z589, B0Z5H3, B1AR13, B1NWE8, B2LMJ1, O19048, O19137, O95639, P0C7P0, P0DI19, P46292, P60335, P83870, P83871, P98138, Q09G48, Q0G9M1, Q0WMV8, Q15365, Q1KXW1, Q332Y0, Q5E9A3, Q5FVR7, Q5R654, Q63789, Q66KE3, Q68S08, Q6DJP7

Diamond homologs: B1AR13, P0C7P0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	81
Likely benign	32
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

499 predictions. Top by Δscore:

Variant	Effect	Δscore
17:38735596:CCGTT:C	acceptor_gain	1.0000
17:38735597:CGTT:C	acceptor_gain	1.0000
17:38735597:CGTTC:C	acceptor_gain	1.0000
17:38735598:GTT:G	acceptor_gain	1.0000
17:38735599:TT:T	acceptor_gain	1.0000
17:38735601:C:CC	acceptor_gain	1.0000
17:38735601:C:CG	acceptor_loss	1.0000
17:38735602:T:G	acceptor_loss	1.0000
17:38730716:A:AG	acceptor_gain	0.9900
17:38730717:A:G	acceptor_gain	0.9900
17:38731843:G:GG	donor_gain	0.9900
17:38731311:T:TA	acceptor_gain	0.9800
17:38731435:AGCAG:A	donor_loss	0.9800
17:38731436:GCAGG:G	donor_loss	0.9800
17:38731437:CAGGT:C	donor_loss	0.9800
17:38731438:AG:A	donor_loss	0.9800
17:38731439:GGTGA:G	donor_loss	0.9800
17:38731440:G:A	donor_loss	0.9800
17:38731441:TGAGA:T	donor_loss	0.9800
17:38731906:G:GA	donor_gain	0.9800
17:38730403:CCGGG:C	donor_loss	0.9700
17:38730404:CGGGT:C	donor_loss	0.9700
17:38730405:GGGTG:G	donor_loss	0.9700
17:38730406:GGT:G	donor_loss	0.9700
17:38730407:G:C	donor_loss	0.9700
17:38730408:T:A	donor_loss	0.9700
17:38730409:GAGCA:G	donor_loss	0.9700
17:38731411:G:GA	donor_gain	0.9700
17:38731442:GAGAC:G	donor_loss	0.9700
17:38731883:A:G	donor_gain	0.9700

AlphaMissense

812 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:38733374:G:C	K101N	0.990
17:38733374:G:T	K101N	0.990
17:38731412:G:C	W59C	0.989
17:38731412:G:T	W59C	0.989
17:38733331:T:C	F87S	0.988
17:38731423:G:T	G63V	0.985
17:38731429:G:T	S65I	0.985
17:38733283:G:A	C71Y	0.985
17:38731423:G:A	G63D	0.984
17:38733330:T:C	F87L	0.983
17:38733332:C:A	F87L	0.983
17:38733332:C:G	F87L	0.983
17:38731410:T:A	W59R	0.982
17:38731410:T:C	W59R	0.982
17:38733363:T:C	C98R	0.982
17:38733363:T:A	C98S	0.981
17:38733364:G:C	C98S	0.981
17:38733396:T:A	C109S	0.981
17:38733397:G:C	C109S	0.981
17:38733282:T:A	C71S	0.980
17:38733283:G:C	C71S	0.980
17:38731419:T:C	C62R	0.979
17:38733282:T:C	C71R	0.979
17:38731428:A:C	S65R	0.978
17:38731430:C:A	S65R	0.978
17:38731430:C:G	S65R	0.978
17:38733365:T:G	C98W	0.978
17:38733397:G:A	C109Y	0.978
17:38731419:T:A	C62S	0.977
17:38731420:G:C	C62S	0.977

dbSNP variants (sampled 300 via entrez): RS1000215071 (17:38730592 C>G,T), RS1000227757 (17:38731012 G>A), RS1000257530 (17:38731266 C>T), RS1000711107 (17:38730913 G>A), RS1001158702 (17:38732002 C>T), RS1001212193 (17:38732140 T>G), RS1001230984 (17:38732350 T>C), RS1002226020 (17:38733806 T>A), RS1002286801 (17:38733658 G>A), RS1002319370 (17:38734071 C>A,T), RS1003058969 (17:38729418 G>A), RS1003090286 (17:38729652 C>T), RS1003225700 (17:38734750 G>A), RS1003229373 (17:38735369 G>T), RS1003687402 (17:38734916 G>C)

Disease associations

OMIM: gene MIM:611933 | disease phenotypes: MIM:604928, MIM:618371

GenCC curated gene-disease

Mondo (2): Wolfram syndrome 2 (MONDO:0011502), turnpenny-fry syndrome (MONDO:0032707)

Orphanet (2): Wolfram syndrome (Orphanet:3463), Turnpenny-Fry syndrome (Orphanet:688642)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004185_4	Lung function (FEV1/FVC)	7.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565733	Wolfram Syndrome 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	3
Benzo(a)pyrene	affects methylation, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
NSC 689534	affects binding, decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	increases abundance, increases expression, affects cotreatment	1
Copper	affects binding, decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Methyl Methanesulfonate	decreases expression	1
Naled	affects expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	affects expression	1

Clinical trials (associated diseases)

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