ISCU

Summary

ISCU (iron-sulfur cluster assembly enzyme, HGNC:29882) is a protein-coding gene on chromosome 12q23.3, encoding Iron-sulfur cluster assembly enzyme ISCU (Q9H1K1). Mitochondrial scaffold protein, of the core iron-sulfur cluster (ISC) assembly complex, that provides the structural architecture on which the [2Fe-2S] clusters are assembled. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

This gene encodes a component of the iron-sulfur (Fe-S) cluster scaffold. Fe-S clusters are cofactors that play a role in the function of a diverse set of enzymes, including those that regulate metabolism, iron homeostasis, and oxidative stress response. Alternative splicing results in transcript variants encoding different protein isoforms that localize either to the cytosol or to the mitochondrion. Mutations in this gene have been found in patients with hereditary myopathy with lactic acidosis. A disease-associated mutation in an intron may activate a cryptic splice site, resulting in the production of a splice variant encoding a putatively non-functional protein. A pseudogene of this gene is present on chromosome 1.

Source: NCBI Gene 23479 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 201 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 35
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_213595

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29882
Approved symbol	ISCU
Name	iron-sulfur cluster assembly enzyme
Location	12q23.3
Locus type	gene with protein product
Status	Approved
Aliases	ISU2, hnifU
Ensembl gene	ENSG00000136003
Ensembl biotype	protein_coding
OMIM	611911
Entrez	23479

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 7 protein_coding, 5 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000311893, ENST00000392807, ENST00000431221, ENST00000535405, ENST00000535729, ENST00000538193, ENST00000539580, ENST00000539593, ENST00000540154, ENST00000544493, ENST00000545932, ENST00000547005, ENST00000552072, ENST00000948249

RefSeq mRNA: 5 — MANE Select: NM_213595 NM_001301140, NM_001301141, NM_001320042, NM_014301, NM_213595

CCDS: CCDS44966, CCDS73518, CCDS76597, CCDS9118

Canonical transcript exons

ENST00000311893 — 5 exons

Exon	Start	End
ENSE00003497077	108568831	108569368
ENSE00003502794	108564279	108564392
ENSE00003540589	108567190	108567268
ENSE00003678625	108565321	108565431
ENSE00003901503	108562596	108562736

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 99.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 101.9265 / max 593.9629, expressed in 1825 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
127886	100.1896	1825
127885	1.7369	979

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	99.71	gold quality
pons	UBERON:0000988	99.70	gold quality
renal medulla	UBERON:0000362	99.59	gold quality
superior vestibular nucleus	UBERON:0007227	99.51	gold quality
substantia nigra pars compacta	UBERON:0001965	99.50	gold quality
lateral globus pallidus	UBERON:0002476	99.47	gold quality
right adrenal gland cortex	UBERON:0035827	99.47	gold quality
myocardium	UBERON:0002349	99.45	gold quality
adrenal cortex	UBERON:0001235	99.43	gold quality
right adrenal gland	UBERON:0001233	99.42	gold quality
left adrenal gland	UBERON:0001234	99.40	gold quality
left adrenal gland cortex	UBERON:0035825	99.40	gold quality
seminal vesicle	UBERON:0000998	99.38	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.38	gold quality
left ventricle myocardium	UBERON:0006566	99.37	gold quality
adult organism	UBERON:0007023	99.37	gold quality
urethra	UBERON:0000057	99.36	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.33	gold quality
apex of heart	UBERON:0002098	99.30	gold quality
cardiac ventricle	UBERON:0002082	99.29	gold quality
heart left ventricle	UBERON:0002084	99.28	gold quality
vena cava	UBERON:0004087	99.28	gold quality
nephron tubule	UBERON:0001231	99.27	gold quality
pituitary gland	UBERON:0000007	99.23	gold quality
parotid gland	UBERON:0001831	99.23	gold quality
thymus	UBERON:0002370	99.23	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.23	gold quality
postcentral gyrus	UBERON:0002581	99.22	gold quality
adrenal gland	UBERON:0002369	99.21	gold quality
calcaneal tendon	UBERON:0003701	99.21	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	25.53
E-MTAB-8142	yes	17.23
E-HCAD-25	yes	9.72
E-MTAB-6379	no	842.65
E-MTAB-6819	no	302.69
E-MTAB-8060	no	184.04
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TBP, ZNF335

miRNA regulators (miRDB)

38 targeting ISCU, 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-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-182-3P	99.57	67.57	825
HSA-MIR-892A	99.54	68.16	1141
HSA-MIR-892C-5P	99.16	70.56	2116

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 37)

• Data suggest that frataxin may be involved in the biosynthesis of iron-sulphur proteins such as IscU1 not only within the mitochondria, but also in the extramitochondrial compartment. (PMID:16091420)
• Functional analysis of the mitochondrial and cytosolic isoforms of the human Fe-S cluster scaffold protein, ISCU. (PMID:16517407)
• the cytosolic form of ISCS is a functional cysteine desulfurase that can collaborate with cytosolic ISCU to promote de novo iron-sulfur cluster formation (PMID:16527810)
• Intron mutation in the ISCU gene, leading to incorrectly spliced mRNA, is the cause of myopathy with lactic acidosis in this family. (PMID:18296749)
• Gene ISCU was identified as a candidate within a region of shared homozygosity among patients with myopathy with severe exercise intolerance and myoglobinuria. (PMID:18304497)
• the iron-dependent binding affinity of each frataxin derivative to the iron-sulfur cluster scaffold protein ISU is found to be similar to that of native frataxin (PMID:18425540)
• a new ISCU mutation in iron-sulphur cluster deficiency myopathy (PMID:19567699)
• Results identify the iron-sulfur cluster assembly proteins (ISCU1/2) as direct targets for repression by the hypoxia-induced microRNA-210. (PMID:19808020)
• miR-210 mediates a new mechanism of adaptation to hypoxia, by regulating mitochondrial function via iron-sulfur cluster metabolism and free radical generation (PMID:20436681)
• ISCU and COX10 are target genes of miR-210 related to mitochondrial metabolism (PMID:20498629)
• Data show that the highest level of incorrectly spliced ISCU mRNA was found in skeletal muscle. (PMID:21165651)
• Exchange of [2Fe-2S] centers between glutaredoxin 2 and the cluster scaffold protein ISU, supports a direct link for glutaredoxin 2 and glutathione involvement in ISU promoted Fe-S cluster biosynthesis. (PMID:21437321)
• iron-sulfur cluster scaffold homologue down-regulation by miR-210 perturbing trophoblast iron metabolism is associated with defective placentation (PMID:21801864)
• The defective splicing caused by the ISCU intron mutation in patients with myopathy with lactic acidosis is repressed by PTBP1 but can be derepressed by IGF2BP1. (PMID:22125086)
• Photoreactive heterotrifunctional chemical cross-linking confirmed the interaction between frataxin and ISCU in the presence of iron and validated that transient interactions can be covalently trapped with this method. (PMID:22897349)
• this study unveiled a signaling axis of HIF-1alpha/miRNA-210/iron-sulfur cluster scaffold protein in a subset of head and neck paragangliomas that could have an impact on SDHB protein stability by a mechanism independent of succinate dehydrogenase mutations (PMID:22977270)
• ISCU protein deficiency in patients results from muscle-specific mis-splicing and oxidative stress. (PMID:23035118)
• MicroRNA-210 correlates negatively with its gene target ISCU at the protein and mRNA level. MicroRNA-210 correlated with positive outcome variables (PMID:23449350)
• mTORC1 associates with ISCU and phosphorylates ISCU at serine 14. This phosphorylation stabilized ISCU protein. (PMID:23508953)
• NFS1 binds preferentially to the D-state of ISCU while mtHSP70 binds preferentially to the D-state of ISCU and HSC20 binds preferentially to the S-state of ISCU. (PMID:23940031)
• the G50E iron-sulfur cluster scaffold protein (ISCU) mutation has a role in mitochondrial myopathy (PMID:24573684)
• Fe-S assembly protein (ISCU2) and frataxin convert substrates l-cysteine, ferrous iron, and electrons into Fe-S clusters. (PMID:24971490)
• IscU is a new substrate of MK2 both in Drosophila cells and in human cells (PMID:25204651)
• Thus, driven by acquired (hypoxia) or genetic causes, the miR-210-ISCU1/2 regulatory axis is a pathogenic lynchpin causing iron-sulfur deficiency and pulmonary hypertension. (PMID:25825391)
• The core Fe-S biosynthetic enzymatic complex generated [2Fe-2S] cluster intermediates that converted to stable [2Fe-2S] clusters bound to uncomplexed ISCU2. (PMID:26016389)
• ISCU expression was decreased in the majority of human liver cancer tissues, and its reduced expression was significantly associated with p53 mutation. (PMID:26560363)
• Molecular dynamics flexible fitting of protein structures docked into the EM map of the model revealed a [FXN(42-210)]24.[NFS1]24.[ISD11]24.[ISCU]24 complex, consistent with the measured 1:1:1:1 stoichiometry of its four components. (PMID:27519411)
• We have shown that ASO treatment diminished aberrant splicing and increased ISCU protein levels in both patient fibroblasts and patient myotubes in a concentration dependent fashion. Upon ASO treatment, levels of SDHB in patient myotubular cell lines increased to levels observed in control myotubular cell lines (PMID:28007899)
• The NFS1/ISD11 complex further interacts with scaffold protein ISCU and regulator protein frataxin, thereby forming a quaternary complex for Fe-S cluster formation. (PMID:28271877)
• we report the first heterozygous dominant mutation in ISCU; notably, this alteration resulted in a similar phenotype as the recessive ISCU disease previously described. (PMID:29079705)
• When ISCU was replaced by the fully structured variant ISCU(M108I), the addition of rdFDX2 to the [NIA-ISCU(M108I)-FXN]2 complex led to the release of FXN. Thus, the displacement of FXN by rdFDX2 explains the failure of FXN to stimulate Fe-S cluster assembly on ISCU(M108I). (PMID:29406711)
• identifies an important regulatory role for zinc-bound ISCU in modulation of the human Fe-S assembly system in vitro and reports no ‘FXN bypass’ effect on mutations at position Met140 in human ISCU (PMID:30031876)
• Study reports 3.2 A resolution cryo-electron microscopy structure of the FXN-bound active human iron-sulfur clusters biosynthesis complex. FXN binds at the interface of two NFS1 and one ISCU subunits, modifying the local environment of a bound zinc ion that would otherwise inhibit NFS1 activity in complexes without FXN. (PMID:31101807)
• rs2072580T>A Polymorphism in the Overlapping Promoter Regions of the SART3 and ISCU Genes Associated with the Risk of Breast Cancer. (PMID:32495170)
• Characterization and Reconstitution of Human Lipoyl Synthase (LIAS) Supports ISCA2 and ISCU as Primary Cluster Donors and an Ordered Mechanism of Cluster Assembly. (PMID:33562493)
• N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synthesis by ISCU2 dimerization. (PMID:34824239)
• Copper exerts cytotoxicity through inhibition of iron-sulfur cluster biogenesis on ISCA1/ISCA2/ISCU assembly proteins. (PMID:37225108)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	iscub	ENSDARG00000026582
danio_rerio	iscua	ENSDARG00000035596
mus_musculus	Iscu	ENSMUSG00000025825
rattus_norvegicus	Iscu	ENSRNOG00000000701
drosophila_melanogaster	IscU	FBGN0037637
caenorhabditis_elegans		WBGENE00012885

Protein

Protein identifiers

Iron-sulfur cluster assembly enzyme ISCU — Q9H1K1 (reviewed: Q9H1K1)

Alternative names: NifU-like N-terminal domain-containing protein, NifU-like protein

All UniProt accessions (5): B3KQ30, Q9H1K1, B4DNC9, F5H5N2, F5H672

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial scaffold protein, of the core iron-sulfur cluster (ISC) assembly complex, that provides the structural architecture on which the [2Fe-2S] clusters are assembled. The core iron-sulfur cluster (ISC) assembly complex is involved in the de novo synthesis of a [2Fe-2S] cluster, the first step of the mitochondrial iron-sulfur protein biogenesis. This process is initiated by the cysteine desulfurase complex (NFS1:LYRM4:NDUFAB1) that produces persulfide which is delivered on the scaffold protein ISCU in a FXN-dependent manner. Then this complex is stabilized by FDX2 which provides reducing equivalents to accomplish the [2Fe-2S] cluster assembly. Finally, the [2Fe-2S] cluster is transferred from ISCU to chaperone proteins, including HSCB, HSPA9 and GLRX5. Exists as two slow interchanging conformational states, a structured (S) and disordered (D) form. May modulate NFS1 desulfurase activity in a zinc-dependent manner. Modulates the interaction between FXN and the cysteine desulfurase complex. Cytoplasmic scaffold protein, of the cytoplasmic core iron-sulfur cluster (ISC) assembly complex that provides the structural architecture on which the Fe-S clusters are assembled and may be involved in the cytoplasmic iron-sulfur protein biogenesis.

Subunit / interactions. Homodimer; Tyr-35-mediated dimerization of two iron- and sulfide-containing ISCU subunit bind to the cysteine desulfurase complex. Component of the mitochondrial core iron-sulfur cluster (ISC) complex composed of NFS1, LYRM4, NDUFAB1, ISCU, FXN, and FDX2; this complex is an heterohexamer containing two copies of each monomer. Interacts (D-state) with NFS1 (homodimer form); each monomer interacts with the C-terminal regions of each NFS1 monomer. Interacts (monomer form) with FXN (via ferrous form); the interaction is possible when both are bound to the dimeric form of the cysteine desulfurase complex (NFS1:LYRM4) and enhances FXN interaction to the dimeric form of the cysteine desulfurase complex (NFS1:LYRM4). Interacts with GLRX5. Interacts (D-state) with HSPA9. Interacts (S-state) with HSCB; this interaction stimulates the ATPase activity of HSPA9. Component of the cytoplasmic core iron-sulfur cluster (ISC) complex composed at least of NFS1, LYRM4, and ISCU; this complex interacts with FXN. Monomer; each monomer binds to the C-terminal regions of NFS1 (cytoplasmic and homodimer form). Interacts with NFS1 (cytoplasmic and homodimer form); this interaction promotes de novo iron-sulfur cluster formation. Interacts with HSCB (cytoplasmic form); this interaction stabilizes the (Fe-S) clusters on ISCU.

Subcellular location. Mitochondrion Cytoplasm. Nucleus.

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

Post-translational modifications. Phosphorylation at Ser-14 is required for ISCU protein stabilization in the cytosol, whereas dephosphorylation of Ser-14, due to the inhibition of mTORC1 (mammalian target of rapamycin complex 1) complex, leads to degradation of the precursor form and ultimately to a decrease in the mitochondrial mature form. Cysteine persulfide is reduced by thiol-containing molecules such as glutathione and L-cysteine.

Disease relevance. Myopathy with exercise intolerance Swedish type (MEIS) [MIM:255125] Autosomal recessive metabolic disease characterized by lifelong severe exercise intolerance, in which minor exertion causes fatigue of active muscles, shortness of breath, and cardiac palpitations in association with lactic acidosis. The biochemical phenotype is characterized by a deficiency in mitochondrial iron-sulfur proteins and impaired muscle oxidative metabolism. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the NifU family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H1K1-1	1, ISCU2	yes
Q9H1K1-2	2, ISCU1

RefSeq proteins (5): NP_001288069, NP_001288070, NP_001306971, NP_055116, NP_998760* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002871	NIF_FeS_clus_asmbl_NifU_N	Domain
IPR011339	ISCU	Family

Pfam: PF01592

UniProt features (45 total): mutagenesis site 16, helix 7, binding site 6, strand 5, modified residue 3, active site 2, transit peptide 1, chain 1, splice variant 1, sequence variant 1, sequence conflict 1, site 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
6UXE	X-RAY DIFFRACTION	1.57
6W1D	X-RAY DIFFRACTION	1.79
6WIH	X-RAY DIFFRACTION	1.9
6WI2	X-RAY DIFFRACTION	1.95
8TVT	X-RAY DIFFRACTION	2
8RMC	ELECTRON MICROSCOPY	2.26
8RMF	ELECTRON MICROSCOPY	2.33
8RMG	ELECTRON MICROSCOPY	2.46
8PK8	ELECTRON MICROSCOPY	2.49
8RME	ELECTRON MICROSCOPY	2.49
7RTK	X-RAY DIFFRACTION	2.5
8RMD	ELECTRON MICROSCOPY	2.52
8PK9	ELECTRON MICROSCOPY	2.58
8PKA	ELECTRON MICROSCOPY	2.75
5WKP	X-RAY DIFFRACTION	3.15
6NZU	ELECTRON MICROSCOPY	3.2
5WLW	X-RAY DIFFRACTION	3.32
5KZ5	ELECTRON MICROSCOPY	14.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H1K1-F1	85.17	0.70

Functional residue map

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

Catalytic / active sites (3): 69 (cysteine persulfide intermediate); 138 (cysteine persulfide intermediate); 35 (mediates iscu dimerization and de novo [2fe-2s] cluster assembly)

Ligand- & substrate-binding residues (6): 71; 46; 70; 112; 95; 138

Post-translational modifications (3): 138, 14, 69

Mutagenesis-validated functional residues (16):

Position	Phenotype
14	loss of phosphorylation. does not affect phosphorylation.
35	does not affect mitochondrial localization. loss of iron-sulfur cluster biogenesis. does not affect reductive cleavage o
69	does not affect isc complex formation. does not affect the unstimulated cysteine desulfurase activity in the absence of
69	does not affect the cysteine desulfurase activity in the presence of fxn. does not affect iron based stimulation of the
71	stabilizes the d-state.
71	stabilizes the s-state.
95	does not affect isc complex formation. does not affect the unstimulated cysteine desulfurase activity in the absence of
95	slightly decrease the cysteine desulfurase activity in the presence of fxn. does not affect iron based stimulation of th
122	stabilizes the s-state.
130	does not affect the unstimulated cysteine desulfurase activity in the absence of fxn. does not affect the cysteine desul
137	stabilizes the d-state.
138	does not affect isc complex formation. does not affect the unstimulated cysteine desulfurase activity in the absence of
138	loss of iron-based stimulation of the cysteine desulfurase activity in the presence of fxn.
140	does not affect the sda complex formation. abolishes desulfurase activity of sda complex when zinc ion is bound. activat

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-9694301	Maturation of replicase proteins
R-HSA-1362409	Mitochondrial iron-sulfur cluster biogenesis
R-HSA-9854311	Maturation of TCA enzymes and regulation of TCA cycle
R-HSA-9865881	Complex III assembly
R-HSA-1643685	Disease
R-HSA-5663205	Infectious disease
R-HSA-9679506	SARS-CoV Infections
R-HSA-9694516	SARS-CoV-2 Infection
R-HSA-9694676	Translation of Replicase and Assembly of the Replication Transcription Complex
R-HSA-9772572	Early SARS-CoV-2 Infection Events
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 307 (showing top): GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, PAX4_01, MORF_RAB5A, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, TGACCTY_ERR1_Q2, GOBP_IRON_ION_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, CEBALLOS_TARGETS_OF_TP53_AND_MYC_DN, YY1_02, GOBP_OXIDATIVE_PHOSPHORYLATION, TGCTGAY_UNKNOWN

GO Biological Process (6): intracellular iron ion homeostasis (GO:0006879), iron-sulfur cluster assembly (GO:0016226), [2Fe-2S] cluster assembly (GO:0044571), [4Fe-4S] cluster assembly (GO:0044572), positive regulation of mitochondrial electron transport, NADH to ubiquinone (GO:1902958), negative regulation of iron ion import across plasma membrane (GO:1904439)

GO Molecular Function (10): iron ion binding (GO:0005506), ferrous iron binding (GO:0008198), zinc ion binding (GO:0008270), protein homodimerization activity (GO:0042803), 2 iron, 2 sulfur cluster binding (GO:0051537), molecular adaptor activity (GO:0060090), iron-sulfur cluster chaperone activity (GO:0140132), protein binding (GO:0005515), metal ion binding (GO:0046872), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (7): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), mitochondrial [2Fe-2S] assembly complex (GO:0099128), iron-sulfur cluster assembly complex (GO:1990229)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Translation of Replicase and Assembly of the Replication Transcription Complex	1
Metabolism	1
Citric acid cycle (TCA cycle)	1
Respiratory electron transport	1
Disease	1
Viral Infection Pathways	1
SARS-CoV Infections	1
Early SARS-CoV-2 Infection Events	1
SARS-CoV-2 Infection	1
Infectious disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
iron-sulfur cluster assembly	2
transition metal ion binding	2
iron-sulfur cluster binding	2
binding	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
metallo-sulfur cluster assembly	1
mitochondrial electron transport, NADH to ubiquinone	1
positive regulation of cellular respiration	1
regulation of mitochondrial electron transport, NADH to ubiquinone	1
negative regulation of iron ion transmembrane transport	1
iron ion import across plasma membrane	1
regulation of iron ion import across plasma membrane	1
iron ion binding	1
identical protein binding	1
protein dimerization activity	1
molecular_function	1
metallochaperone activity	1
cation binding	1
metal cluster binding	1
intracellular anatomical structure	1
mitochondrion	1
intracellular organelle lumen	1
mitochondrial protein-containing complex	1
L-cysteine desulfurase complex	1
iron-sulfur cluster assembly complex	1
protein-containing complex	1

Protein interactions and networks

STRING

2392 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ISCU	LYRM4	Q9HD34	999
ISCU	NFS1	Q9Y697	999
ISCU	FXN	Q16595	997
ISCU	HSPA9	P30036	938
ISCU	ACO1	P21399	936
ISCU	ACO2	Q99798	924
ISCU	NFU1	Q9UMS0	917
ISCU	HSCB	Q8IWL3	900
ISCU	ISCA2	Q86U28	879
ISCU	FDX2	Q6P4F2	876
ISCU	FDX1	P10109	853
ISCU	ISCA1	Q9BUE6	843
ISCU	FECH	P22830	829
ISCU	IBA57	Q5T440	808
ISCU	IREB2	P48200	800

IntAct

120 interactions, top by confidence:

A	B	Type	Score
SDHB	SDHA	psi-mi:“MI:0914”(association)	0.820
HSCB	SDHB	psi-mi:“MI:0914”(association)	0.820
HSCB	SDHB	psi-mi:“MI:0915”(physical association)	0.820
SDHAF1	SDHB	psi-mi:“MI:0914”(association)	0.790
SDHB	SDHAF1	psi-mi:“MI:0914”(association)	0.790
HSCB	HSPA9	psi-mi:“MI:0914”(association)	0.740
ISCU	NUP62	psi-mi:“MI:0915”(physical association)	0.720
NUP62	ISCU	psi-mi:“MI:0915”(physical association)	0.720
ISCU	HPRT1	psi-mi:“MI:0915”(physical association)	0.670
HPRT1	ISCU	psi-mi:“MI:0915”(physical association)	0.670
SDHB	HSPA9	psi-mi:“MI:0914”(association)	0.660
SDHB	ISCU	psi-mi:“MI:0915”(physical association)	0.660
HSPA9	SDHB	psi-mi:“MI:0915”(physical association)	0.660
LYRM4	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610

BioGRID (59): ISCU (Two-hybrid), ISCU (Two-hybrid), ISCU (Two-hybrid), ISCU (Two-hybrid), NUP62 (Two-hybrid), NECAB2 (Two-hybrid), BANP (Two-hybrid), AGTRAP (Two-hybrid), LNX1 (Two-hybrid), KRT40 (Two-hybrid), FAM9B (Two-hybrid), CCDC172 (Two-hybrid), ISCU (Reconstituted Complex), ISCU (Reconstituted Complex), HSCB (Affinity Capture-Western)

ESM2 similar proteins: A2BP63, A2BUP5, A3PAY5, A8G223, B0YLW7, B4EVE1, B7J1T7, O31270, O32163, O49627, O51339, O51885, O67045, O81433, P05343, P0ACD4, P0ACD5, P0ACD6, P0ACD7, P20628, P23121, P23307, P32582, P57658, Q03020, Q04F14, Q0SNF0, Q12056, Q1RH78, Q31CR8, Q31DE7, Q43885, Q57074, Q6BGU0, Q6CFQ0, Q6CRQ9, Q75C07, Q7N5Z7, Q7V329, Q7V3N7

Diamond homologs: B0YLW7, O31270, O32163, O49627, O51885, O67045, O81433, P05340, P05343, P0ACD4, P0ACD5, P0ACD6, P0ACD7, P0DMG1, P0DMG2, P20628, P23121, P57658, Q03020, Q12056, Q43885, Q43909, Q57074, Q6BGU0, Q6CFQ0, Q6CRQ9, Q6FJY3, Q75C07, Q89A18, Q8IKT4, Q8LR34, Q8SSM2, Q9A1G2, Q9D7P6, Q9H1K1, Q9MAB6, Q9UTC6, Q9VHK6, Q9ZD61, Q01180

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MTOR	up-regulates	ISCU	phosphorylation
mTORC1	up-regulates	ISCU	phosphorylation
ISCU	“form complex”	“Mitochondrial Fe-S Cluster Assembly Complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 61 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
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	112.0×	2e-13
Activation of BAD and translocation to mitochondria	7	111.0×	7e-12
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	98.0×	2e-11
Activation of BH3-only proteins	7	72.4×	1e-10
RHO GTPases activate PKNs	9	59.5×	2e-12
Maturation of TCA enzymes and regulation of TCA cycle	5	59.5×	4e-07
Complex III assembly	6	54.9×	3e-08
Intrinsic Pathway for Apoptosis	7	42.7×	7e-09

GO biological processes:

GO term	Partners	Fold	FDR
iron-sulfur cluster assembly	5	56.8×	8e-06
protein targeting	5	34.6×	4e-05
intracellular protein localization	7	13.8×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	63
Likely benign	93
Benign	36

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
223141	NM_213595.4(ISCU):c.418+382G>C	Pathogenic
783	NM_213595.4(ISCU):c.149G>A (p.Gly50Glu)	Likely pathogenic

SpliceAI

803 predictions. Top by Δscore:

Variant	Effect	Δscore
12:108562733:GAAG:G	donor_gain	1.0000
12:108562736:GGTAG:G	donor_loss	1.0000
12:108562737:GTA:G	donor_loss	1.0000
12:108562738:T:G	donor_loss	1.0000
12:108564273:TTTTA:T	acceptor_loss	1.0000
12:108564274:TTTA:T	acceptor_loss	1.0000
12:108564277:AGG:A	acceptor_loss	1.0000
12:108564278:G:A	acceptor_loss	1.0000
12:108564278:GGTT:G	acceptor_gain	1.0000
12:108564376:AC:A	donor_gain	1.0000
12:108564388:TACAG:T	donor_loss	1.0000
12:108564389:ACAGG:A	donor_loss	1.0000
12:108564390:CAG:C	donor_loss	1.0000
12:108564391:AGGTA:A	donor_loss	1.0000
12:108564392:GGTAT:G	donor_loss	1.0000
12:108564393:GT:G	donor_loss	1.0000
12:108564394:T:G	donor_loss	1.0000
12:108565425:A:T	donor_gain	1.0000
12:108565428:GACG:G	donor_gain	1.0000
12:108567180:T:G	acceptor_gain	1.0000
12:108567184:TCTCA:T	acceptor_loss	1.0000
12:108567185:CTCA:C	acceptor_loss	1.0000
12:108567188:A:AT	acceptor_loss	1.0000
12:108567264:CTCCA:C	donor_gain	1.0000
12:108567265:TCCAG:T	donor_loss	1.0000
12:108567266:CCA:C	donor_gain	1.0000
12:108567267:CA:C	donor_gain	1.0000
12:108567267:CAG:C	donor_loss	1.0000
12:108567268:AG:A	donor_loss	1.0000
12:108567269:G:GG	donor_gain	1.0000

AlphaMissense

1064 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:108564343:G:A	G60E	1.000
12:108564373:G:A	G70D	1.000
12:108564373:G:T	G70V	1.000
12:108565360:T:C	F90L	1.000
12:108565362:T:A	F90L	1.000
12:108565362:T:G	F90L	1.000
12:108565369:T:C	F93L	1.000
12:108565371:T:A	F93L	1.000
12:108565371:T:G	F93L	1.000
12:108565372:G:C	G94R	1.000
12:108565373:G:A	G94D	1.000
12:108565373:G:T	G94V	1.000
12:108565375:T:C	C95R	1.000
12:108565388:T:A	I99N	1.000
12:108565391:C:A	A100D	1.000
12:108565396:A:C	S102R	1.000
12:108565398:C:A	S102R	1.000
12:108565398:C:G	S102R	1.000
12:108567262:T:C	C138R	1.000
12:108567263:G:A	C138Y	1.000
12:108567264:C:G	C138W	1.000
12:108567266:C:T	S139F	1.000
12:108564312:G:T	G50W	0.999
12:108564313:G:A	G50E	0.999
12:108564349:G:A	G62E	0.999
12:108564357:G:A	G65R	0.999
12:108564357:G:C	G65R	0.999
12:108564357:G:T	G65W	0.999
12:108564358:G:A	G65E	0.999
12:108564369:T:C	C69R	0.999

dbSNP variants (sampled 300 via entrez): RS1000037162 (12:108559938 C>T), RS1000201270 (12:108560334 T>C), RS1000316305 (12:108560637 G>A,T), RS1001183084 (12:108566028 C>G,T), RS1001541880 (12:108565502 T>A), RS1001658224 (12:108565849 G>A), RS1002092867 (12:108559652 G>A), RS1002405147 (12:108561684 T>C), RS1002953753 (12:108569593 G>A,T), RS1003219323 (12:108563829 T>A), RS1004254353 (12:108560467 A>G), RS1004659787 (12:108566795 T>C), RS1004674167 (12:108560713 A>C,G), RS1005025487 (12:108566402 C>A), RS1005326305 (12:108563507 G>C)

Disease associations

OMIM: gene MIM:611911 | disease phenotypes: MIM:255125

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary myopathy with lactic acidosis due to ISCU deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (2): myopathy (MONDO:0005336), hereditary myopathy with lactic acidosis due to ISCU deficiency (MONDO:0009706)

Orphanet (1): Hereditary myopathy with lactic acidosis due to ISCU deficiency (Orphanet:43115)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000597	Ophthalmoparesis
HP:0001252	Hypotonia
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001324	Muscle weakness
HP:0001488	Bilateral ptosis
HP:0001882	Decreased total leukocyte count
HP:0001903	Anemia
HP:0001924	Sideroblastic anemia
HP:0001962	Palpitations
HP:0002094	Dyspnea
HP:0002151	Increased circulating lactate concentration
HP:0002359	Frequent falls
HP:0002460	Distal muscle weakness
HP:0002913	Myoglobinuria
HP:0003128	Lactic acidosis
HP:0003198	Myopathy
HP:0003201	Rhabdomyolysis
HP:0003202	Skeletal muscle atrophy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003388	Easy fatigability
HP:0003394	Muscle spasm
HP:0003546	Exercise intolerance
HP:0003548	Subsarcolemmal accumulations of abnormally shaped mitochondria
HP:0003557	Increased variability in muscle fiber diameter
HP:0003621	Juvenile onset
HP:0003737	Mitochondrial myopathy
HP:0008306	Abnormal iron deposition in mitochondria
HP:0008314	Decreased activity of mitochondrial complex II

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002481_2	Acne (severe)	5.000000e-06
GCST005580_119	Intraocular pressure	5.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564972	Myopathy with Lactic Acidosis, Hereditary (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects expression, increases expression, increases methylation	5
sodium arsenite	affects cotreatment, increases abundance, increases expression	3
Acetaminophen	affects cotreatment, decreases expression, increases expression	3
Cisplatin	affects cotreatment, increases expression	3
bisphenol A	affects expression, affects cotreatment, increases expression	2
perfluorooctane sulfonic acid	increases expression	2
Benzo(a)pyrene	increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
chloroacetaldehyde	decreases expression	1
triphenyl phosphate	affects expression	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	increases expression	1
K 7174	increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
ICG 001	increases expression	1
jinfukang	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	decreases expression	1
Cidofovir	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Atrazine	decreases expression	1
Carbamazepine	affects expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diazinon	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120055	PHASE4	COMPLETED	Association Between Systemic Exposure of Atorvastatin and Metabolites and Atorvastatin-induced Myotoxicity
NCT03633565	PHASE4	UNKNOWN	Comparative Study of Strategies for Management of Duchenne Myopathy (DM)
NCT01225614	PHASE3	UNKNOWN	Efficacy and Tolerance of Early Launching of Nocturnal Non Invasive
NCT00278564	PHASE1	TERMINATED	Stem Cell Transplantation in Idiopathic Inflammatory Myopathy Diseases
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT02124070	PHASE1/PHASE2	WITHDRAWN	Therapeutic Effect of Recombinant Human Growth Hormone (rhGH) on the Myopathy of Cystinosis
NCT00549029	Not specified	UNKNOWN	The Association of Genetic Polymorphisms With Statin-Induced Myopathy.
NCT00767130	Not specified	UNKNOWN	DNA Diagnostic System for Statin Safety and Efficacy
NCT00922428	Not specified	COMPLETED	PASCOE-Agil HOM-Injektopas in the Treatment of Rheumatic Disorders
NCT00937001	Not specified	ACTIVE_NOT_RECRUITING	Critical Illness Myopathy as a Cause of Debilitating ICU-Acquired Weakness
NCT00990834	Not specified	WITHDRAWN	Muscle Characteristics Associated With Statin Therapy
NCT01022450	Not specified	UNKNOWN	Study of the Causes of the Breakdown of Muscle Fibers in Hospitalized Patients
NCT01040650	Not specified	TERMINATED	Metabolic Features of Post-Myopathy Patients Associated With Statin Treatment
NCT01047163	Not specified	COMPLETED	Maintenance of Muscle Mass in Older People: the Negative Impact of Statin Therapy
NCT01270269	Not specified	COMPLETED	ACT-ICU Study: Activity and Cognitive Therapy in the Intensive Care Unit
NCT01353430	Not specified	RECRUITING	Characterization of Inclusion Body Myopathy Associated With Paget’s Disease of Bone and Frontotemporal Dementia (IBMPFD)
NCT01395563	Not specified	WITHDRAWN	Strength Training on Pancreatic Cancer
NCT01530841	Not specified	COMPLETED	Efficacy and Tolerance of AVAPS Mode in Myotonic Dystrophy
NCT01547767	Not specified	COMPLETED	Investigations Into ISCU Myopathy or Iron Sulfur Scaffold U Protein Myopathy
NCT01702987	Not specified	COMPLETED	Evaluation of Ubiquinol on Mitochondrial Oxidative Capacity in Statin Patients Using 31PMRS
NCT01790178	Not specified	COMPLETED	Ultrasound in Muscle Biopsy
NCT02011282	Not specified	COMPLETED	Electro-Neuro-Muscular Stimulation in ICU
NCT02104921	Not specified	COMPLETED	Innovative Ultrasound Technology in Neuromuscular Disease
NCT02118805	Not specified	COMPLETED	Innovative Measures of Speech and Swallowing Dysfunction in Neurological Disorders
NCT02235220	Not specified	UNKNOWN	Reduction of Masticatory Muscle Activity by Restoring Canine Guidance
NCT02247895	Not specified	TERMINATED	Treatment of Muscle Weakness in Critically Ill Patients
NCT02315339	Not specified	TERMINATED	European Home Mechanical Ventilation Registry
NCT02442986	Not specified	COMPLETED	Neurological Outcome in Surgical and Non-surgical Septic Patients
NCT02706314	Not specified	COMPLETED	Impact of Human Blood Serum From Critically Ill Patients on Human Colon Neuronal Networks.
NCT02765828	Not specified	COMPLETED	Identification of Tongue Involvement in Late-Onset Pompe Disease
NCT03042286	Not specified	UNKNOWN	SAPhIRE Statin Adverse Drug Reaction
NCT03141749	Not specified	COMPLETED	Venous Thromboembolism in DM1
NCT03660969	Not specified	ACTIVE_NOT_RECRUITING	Reliability of Cardiac Troponins for the Diagnosis of Myocardial Infarction in the Presence of Skeletal Muscle Disease
NCT03749538	Not specified	RECRUITING	Acute Transcranial Direct Current Stimulation in Patients With Systemic Autoimmune Myopathies
NCT03751644	Not specified	COMPLETED	Peripherical Neuromuscular Electrical Stimulation in Systemic Autoimmune Myopathies
NCT03998540	Not specified	UNKNOWN	Improvement of DIAgnostic and Phenotype-genotype Correlation Studies in Patients With MYOpathy Suspected of TITinopathy
NCT04678635	Not specified	RECRUITING	Chronic Transcranial Direct Current Stimulation in Patients With Systemic Autoimmune Myopathies
NCT04881214	Not specified	UNKNOWN	COVID-19 Pneumonia: Pulmonary Physiology, Health-related Quality of Life and Benefit of a Rehabilitation Program
NCT04941079	Not specified	UNKNOWN	Safety and Efficacy of Inactivated SARS-CoV-2 Vaccine in Immune-related Myopathy (Myasthenia Gravis and Inflammatory Myopathy) Patients ：a Prospective Observational Study
NCT05599568	Not specified	RECRUITING	Repeated Bout Effect i Neuromuscular Diseases