NDUFS3

Summary

NDUFS3 (NADH:ubiquinone oxidoreductase core subunit S3, HGNC:7710) is a protein-coding gene on chromosome 11p11.2, encoding NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial (O75489). Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. It is a selective cancer dependency (DepMap: 22.6% of cell lines).

This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone oxidoreductase (complex I). Mutations in this gene are associated with Leigh syndrome resulting from mitochondrial complex I deficiency.

Source: NCBI Gene 4722 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial complex I deficiency, nuclear type 8 (Strong, GenCC) — +4 more curated relationships
• GWAS associations: 23
• Clinical variants (ClinVar): 173 total — 3 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 48
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 22.6% of screened cell lines
• MANE Select transcript: NM_004551

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7710
Approved symbol	NDUFS3
Name	NADH:ubiquinone oxidoreductase core subunit S3
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Aliases	CI-30
Ensembl gene	ENSG00000213619
Ensembl biotype	protein_coding
OMIM	603846
Entrez	4722

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 15 protein_coding, 7 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000263774, ENST00000524568, ENST00000525212, ENST00000525378, ENST00000527178, ENST00000528192, ENST00000529276, ENST00000530295, ENST00000531351, ENST00000533105, ENST00000533507, ENST00000534208, ENST00000534716, ENST00000677462, ENST00000678975, ENST00000892081, ENST00000892082, ENST00000892083, ENST00000892084, ENST00000925066, ENST00000925067, ENST00000925068, ENST00000925069, ENST00000925070, ENST00000961331

RefSeq mRNA: 1 — MANE Select: NM_004551 NM_004551

CCDS: CCDS7941

Canonical transcript exons

ENST00000263774 — 7 exons

Exon	Start	End
ENSE00002142616	47584314	47584562
ENSE00003278869	47579269	47579334
ENSE00003478259	47582349	47582468
ENSE00003561896	47582088	47582213
ENSE00003573507	47580835	47580984
ENSE00003589307	47580525	47580622
ENSE00003908168	47579074	47579158

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 98.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 92.5637 / max 568.7488, expressed in 1828 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114225	92.5637	1828

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
putamen	UBERON:0001874	98.93	gold quality
mucosa of transverse colon	UBERON:0004991	98.88	gold quality
apex of heart	UBERON:0002098	98.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.85	gold quality
primary visual cortex	UBERON:0002436	98.79	gold quality
caudate nucleus	UBERON:0001873	98.77	gold quality
heart left ventricle	UBERON:0002084	98.70	gold quality
prefrontal cortex	UBERON:0000451	98.57	gold quality
gastrocnemius	UBERON:0001388	98.57	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.47	gold quality
nucleus accumbens	UBERON:0001882	98.45	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.40	gold quality
muscle of leg	UBERON:0001383	98.36	gold quality
frontal cortex	UBERON:0001870	98.35	gold quality
frontal lobe	UBERON:0016525	98.35	gold quality
superior frontal gyrus	UBERON:0002661	98.33	gold quality
cerebral cortex	UBERON:0000956	98.26	gold quality
skeletal muscle tissue	UBERON:0001134	98.21	gold quality
anterior cingulate cortex	UBERON:0009835	98.17	gold quality
amygdala	UBERON:0001876	98.16	gold quality
temporal lobe	UBERON:0001871	98.14	gold quality
hypothalamus	UBERON:0001898	98.14	gold quality
right frontal lobe	UBERON:0002810	98.14	gold quality
substantia nigra	UBERON:0002038	98.13	gold quality
brain	UBERON:0000955	98.12	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.12	gold quality
Ammon’s horn	UBERON:0001954	98.05	gold quality
heart	UBERON:0000948	98.03	gold quality
rectum	UBERON:0001052	97.94	gold quality
transverse colon	UBERON:0001157	97.94	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.68
E-MTAB-6386	no	328.02

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 22.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 14)

• Decreased protein levels of complex I 30-kDa subunit in fetal Down syndrome brains. (PMID:11771736)
• This protein has been found differentially expressed in the temporal lobe from patients with schizophrenia. (PMID:19034380)
• a novel, biomarker potential of a mitochondrial complex I subunit protein, NDUFS3 - as a robust indicator of breast cancer progression and invasiveness as well as of hypoxia/necrosis in clinical specimens of invasive ductal carcinoma, was uncovered. (PMID:21867691)
• NDUFS3 is down-regulated in serous ovarian adenocarcinoma (PMID:23446378)
• Expressions of GRIM-19, NDUFS3, and extracellular matrix elements are correlated with invasive capabilities of breast cancer cell lines. (PMID:23630608)
• pH stability of w-t and Leigh syndrome mutant varied at extreme acidic pH. the molten globule like structure of w-t at pH1 was absent in case of the mutant protein. Both the w-t and mutant proteins showed multi-step thermal and Gdn-HCl induced unfolding (PMID:24028823)
• High NDUFS3 expression is associated with IgA nephropathy. (PMID:25770168)
• The NDUFS3 expressed in the temporal cortex in patient with late-onset Alzheimer’s disease. (PMID:28242297)
• We observed loss of NDUFB8 immunoreactivity in all patients with mutations affecting nuclear-encoding structural subunits and assembly factors, whilst only 3 of the 10 patients with mutations affecting mtDNA-encoded structural subunits showed loss of NDUFB8, confirmed by BN-PAGE analysis of CI assembly and IHC using an alternative, commercially-available CI (NDUFS3) antibody. (PMID:29142257)
• The results suggest that the impaired mitochondrial activity could be due to the broken interaction between DJ-1 and NDUFS3 and that downregulation of DJ-1 in sperm and testes contributes to AS pathogenesis. (PMID:29849492)
• identified a novel Leigh syndrome causing NDUFS3 mutation and expanded the clinical spectrum caused by NDUFS3 mutations in this study. (PMID:30140060)
• Biallelic variants in two complex I genes cause abnormal splicing defects in probands with mild Leigh syndrome. (PMID:33097395)
• NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate. (PMID:33882309)
• NDUFB11 and NDUFS3 play a role in atherosclerosis and chronic stress. (PMID:37642954)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufs3	ENSDARG00000015385
mus_musculus	Ndufs3	ENSMUSG00000005510
rattus_norvegicus	Ndufs3	ENSRNOG00000009155
drosophila_melanogaster	ND-30	FBGN0266582
caenorhabditis_elegans	nuo-2	WBGENE00020417

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial — O75489 (reviewed: O75489)

Alternative names: Complex I-30kD, NADH-ubiquinone oxidoreductase 30 kDa subunit

All UniProt accessions (5): E9PJE7, E9PKL8, E9PS48, G3V194, O75489

UniProt curated annotations — full annotation on UniProt →

Function. Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. Essential for the catalytic activity and assembly of complex I.

Subunit / interactions. Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits. Interacts with NDUFAF3. Interacts with RAB5IF. Found in subcomplexes containing subunits NDUFS2, MT-ND1 and NDUFA13.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 8 (MC1DN8) [MIM:618230] A form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN8 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the complex I 30 kDa subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
O75489-1	1	yes
O75489-2	2

RefSeq proteins (1): NP_004542* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001268	NADH_UbQ_OxRdtase_30kDa_su	Domain
IPR010218	NADH_DH_suC	Family
IPR020396	NADH_UbQ_OxRdtase_CS	Conserved_site
IPR037232	NADH_quin_OxRdtase_su_C/D-like	Homologous_superfamily

Pfam: PF00329

Catalyzed reactions (Rhea), 1 shown:

• a ubiquinone + NADH + 5 H(+)(in) = a ubiquinol + NAD(+) + 4 H(+)(out) (RHEA:29091)

UniProt features (29 total): strand 11, helix 5, turn 4, sequence variant 4, splice variant 2, transit peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
9I4I	ELECTRON MICROSCOPY	2.63
9TI4	ELECTRON MICROSCOPY	2.66
5XTB	ELECTRON MICROSCOPY	3.4
9CWT	ELECTRON MICROSCOPY	3.44
5XTD	ELECTRON MICROSCOPY	3.7
5XTH	ELECTRON MICROSCOPY	3.9
5XTI	ELECTRON MICROSCOPY	17.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75489-F1	83.42	0.79

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-611105	Respiratory electron transport
R-HSA-6799198	Complex I biogenesis
R-HSA-9013408	RHOG GTPase cycle
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-392499	Metabolism of proteins
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 426 (showing top): MODULE_93, HONMA_DOCETAXEL_RESISTANCE, MORF_SMC1L1, MODULE_77, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_UBE2I, MORF_HDAC1, MORF_UBE2N, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, MORF_RAD21, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT

GO Biological Process (7): mitochondrial electron transport, NADH to ubiquinone (GO:0006120), aerobic respiration (GO:0009060), substantia nigra development (GO:0021762), mitochondrial respiratory chain complex I assembly (GO:0032981), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), reactive oxygen species metabolic process (GO:0072593), proton transmembrane transport (GO:1902600)

GO Molecular Function (6): NADH dehydrogenase activity (GO:0003954), NADH dehydrogenase (ubiquinone) activity (GO:0008137), electron transfer activity (GO:0009055), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on NAD(P)H (GO:0016651)

GO Cellular Component (8): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), nuclear body (GO:0016604), mitochondrial membrane (GO:0031966), respiratory chain complex I (GO:0045271), sperm principal piece (GO:0097228), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Respiratory electron transport	1
RHO GTPase cycle	1
Metabolism of proteins	1
Metabolism	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	3
cellular anatomical structure	2
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
cellular respiration	1
midbrain development	1
neural nucleus development	1
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	1
metabolic process	1
monoatomic cation transmembrane transport	1
oxidoreductase activity, acting on NAD(P)H	1
NADH dehydrogenase activity	1
electron transfer activity	1
proton transmembrane transporter activity	1
oxidoreduction-driven active transmembrane transporter activity	1
oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor	1
active monoatomic ion transmembrane transporter activity	1
molecular_function	1
binding	1
catalytic activity	1
oxidoreductase activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
intracellular organelle lumen	1
nucleoplasm	1
intracellular membraneless organelle	1
mitochondrial envelope	1
organelle membrane	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1
sperm flagellum	1

Protein interactions and networks

STRING

4621 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFS3	NDUFS2	O75306	999
NDUFS3	NDUFS7	O75251	998
NDUFS3	NDUFS8	O00217	998
NDUFS3	NDUFV1	P49821	997
NDUFS3	NDUFS1	P28331	996
NDUFS3	NDUFV2	P19404	994
NDUFS3	NDUFA9	Q16795	992
NDUFS3	NDUFA5	Q16718	967
NDUFS3	NDUFS6	O75380	955
NDUFS3	NDUFS4	O43181	914
NDUFS3	NDUFB6	O95139	899
NDUFS3	NDUFAF5	Q5TEU4	891
NDUFS3	NDUFA13	Q9P0J0	891
NDUFS3	NDUFA6	P56556	885
NDUFS3	NDUFB9	Q9Y6M9	885

IntAct

183 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS2	psi-mi:“MI:0914”(association)	0.850
NDUFS2	NDUFS3	psi-mi:“MI:0914”(association)	0.850
NDUFS3	NDUFS2	psi-mi:“MI:0915”(physical association)	0.850
NDUFS2	NDUFS3	psi-mi:“MI:0915”(physical association)	0.850
NDUFS3	NDUFA5	psi-mi:“MI:0915”(physical association)	0.840
NDUFAF1	NDUFS3	psi-mi:“MI:0914”(association)	0.790
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
NDUFV2	NDUFS2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFS3	NDUFB6	psi-mi:“MI:0914”(association)	0.640
NDUFB5	NDUFB3	psi-mi:“MI:0914”(association)	0.640
NDUFAF4	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA9	NDUFS4	psi-mi:“MI:0914”(association)	0.640

BioGRID (657): NDUFS3 (Affinity Capture-MS), NDUFS3 (Affinity Capture-RNA), NDUFS3 (Affinity Capture-RNA), NDUFS3 (Affinity Capture-RNA), NDUFS3 (Affinity Capture-MS), NDUFS3 (Affinity Capture-MS), NDUFB1 (Affinity Capture-MS), NDUFV2 (Affinity Capture-MS), NDUFV3 (Affinity Capture-MS), NDUFB10 (Affinity Capture-MS), ND4 (Affinity Capture-MS), NDUFAF1 (Affinity Capture-MS), ECSIT (Affinity Capture-MS), NDUFA7 (Affinity Capture-MS), NDUFB9 (Affinity Capture-MS)

ESM2 similar proteins: A2Z3E5, B4FFK9, F5H9F9, O04064, O75489, P03225, P03407, P04601, P05856, P05858, P05859, P0C742, P10191, P10593, P12479, P16731, P16791, P19546, P20867, P35959, P68342, P68350, P89457, Q05536, Q08356, Q0E1D7, Q0JEF5, Q0MQG6, Q0MQG7, Q0MQG8, Q32LJ5, Q338P6, Q3KSQ7, Q42840, Q42946, Q4JFW8, Q58DR0, Q5REH8, Q652K1, Q6DFN5

Diamond homologs: A0A1D8PJ73, A1TLL8, A1USW9, A1W4M4, A1WLP2, A3PIX0, A4SXQ1, A4WU32, A5VPY5, A6U7W5, A6X1N2, A7HY47, A7IPA5, A8I3Y9, A8LIT7, A9AFY9, A9CJB1, A9IUQ0, A9M3E0, A9MAI1, A9W1N1, B0CLD1, B0SZ50, B0ULK6, B1LUN5, B1XUK0, B1ZA44, B2S545, B2U7Q9, B3PVZ9, B3Q7N4, B4RCM7, B5EN69, B5ZYL4, B7J7U3, B9JD44, B9JVE7, B9KQW2, C0RIE1, O21271

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NDUFS3	“form complex”	“NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 137 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
Complex I biogenesis	30	51.2×	7e-43
Respiratory electron transport	30	29.4×	1e-34
Aerobic respiration and respiratory electron transport	29	26.5×	5e-32
Complex IV assembly	5	11.8×	6e-03
Mitochondrial protein degradation	9	10.6×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	24	72.3×	3e-37
proton motive force-driven mitochondrial ATP synthesis	24	53.1×	2e-33
aerobic respiration	24	50.0×	7e-33
mitochondrial respiratory chain complex I assembly	13	44.9×	2e-16

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	4
Uncertain significance	94
Likely benign	46
Benign	6

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1700108	NM_004551.3(NDUFS3):c.473_474del (p.Ser158fs)	Pathogenic
214807	NM_004551.3(NDUFS3):c.568_569del (p.Asp190fs)	Pathogenic
2258085	NM_004551.3(NDUFS3):c.49dup (p.Ala17fs)	Pathogenic
214805	NM_004551.3(NDUFS3):c.2T>G (p.Met1Arg)	Likely pathogenic
2228564	NM_004551.3(NDUFS3):c.3G>C (p.Met1Ile)	Likely pathogenic
2431418	NM_004551.3(NDUFS3):c.382-1del	Likely pathogenic
3776784	NM_004551.3(NDUFS3):c.418C>G (p.Arg140Gly)	Likely pathogenic

SpliceAI

1590 predictions. Top by Δscore:

Variant	Effect	Δscore
11:47565794:CAGG:C	donor_loss	1.0000
11:47565795:AGG:A	donor_loss	1.0000
11:47565798:T:A	donor_loss	1.0000
11:47565904:A:AG	acceptor_gain	1.0000
11:47565904:AGCT:A	acceptor_gain	1.0000
11:47565905:G:GG	acceptor_gain	1.0000
11:47565905:GCT:G	acceptor_gain	1.0000
11:47565905:GCTG:G	acceptor_gain	1.0000
11:47565987:G:GA	donor_loss	1.0000
11:47569678:A:AG	acceptor_gain	1.0000
11:47569678:ATACT:A	acceptor_gain	1.0000
11:47569680:A:AG	acceptor_gain	1.0000
11:47569680:ACT:A	acceptor_gain	1.0000
11:47569682:T:TA	acceptor_gain	1.0000
11:47569784:G:GT	donor_gain	1.0000
11:47571447:T:A	acceptor_gain	1.0000
11:47573787:TTTC:T	acceptor_gain	1.0000
11:47573787:TTTCC:T	acceptor_loss	1.0000
11:47573788:TTCC:T	acceptor_loss	1.0000
11:47575587:CCTTA:C	donor_loss	1.0000
11:47575588:CTTA:C	donor_loss	1.0000
11:47575589:TTAC:T	donor_loss	1.0000
11:47575590:TA:T	donor_loss	1.0000
11:47575591:A:AC	donor_gain	1.0000
11:47575592:C:CC	donor_gain	1.0000
11:47575592:CCTT:C	donor_gain	1.0000
11:47575696:CCAT:C	acceptor_gain	1.0000
11:47575697:CAT:C	acceptor_gain	1.0000
11:47575697:CATC:C	acceptor_gain	1.0000
11:47575698:ATCTG:A	acceptor_loss	1.0000

AlphaMissense

1708 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:47582355:G:C	D172H	0.999
11:47582356:A:C	D172A	0.999
11:47582356:A:T	D172V	0.999
11:47582398:G:C	R186T	0.999
11:47582398:G:T	R186M	0.999
11:47582418:T:C	F193L	0.999
11:47582420:C:A	F193L	0.999
11:47582420:C:G	F193L	0.999
11:47582437:G:C	R199P	0.999
11:47584401:T:A	W239R	0.999
11:47584401:T:C	W239R	0.999
11:47580609:T:A	V73D	0.998
11:47582399:G:C	R186S	0.998
11:47582399:G:T	R186S	0.998
11:47582404:T:C	L188P	0.998
11:47582445:T:C	F202L	0.998
11:47582447:T:A	F202L	0.998
11:47582447:T:G	F202L	0.998
11:47584377:C:A	R231S	0.998
11:47584383:T:C	F233L	0.998
11:47584385:T:A	F233L	0.998
11:47584385:T:G	F233L	0.998
11:47584403:G:C	W239C	0.998
11:47584403:G:T	W239C	0.998
11:47580902:T:C	L100P	0.997
11:47582199:T:A	W165R	0.997
11:47582199:T:C	W165R	0.997
11:47582365:G:A	G175E	0.997
11:47582395:G:T	R185I	0.997
11:47582396:A:C	R185S	0.997

dbSNP variants (sampled 300 via entrez): RS1000243573 (11:47578514 C>G), RS1000308500 (11:47581584 A>G), RS1000458989 (11:47578743 G>A), RS1000905375 (11:47583840 C>T), RS1000957197 (11:47583376 C>T), RS1001429609 (11:47584979 C>G), RS1002317878 (11:47578999 AGAT>A), RS1002539493 (11:47579856 C>T), RS1002608455 (11:47578738 C>A,G,T), RS1003101537 (11:47583768 C>G,T), RS1003212119 (11:47583043 A>G), RS1003598966 (11:47581113 C>A,T), RS1003809083 (11:47581390 C>T), RS1004214589 (11:47579178 T>A,C), RS1004314489 (11:47578440 G>A)

Disease associations

OMIM: gene MIM:603846 | disease phenotypes: MIM:266265, MIM:618230, MIM:256000, MIM:252010

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 8	Strong	Autosomal recessive
Leigh syndrome	Moderate	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive
mitochondrial complex I deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Moderate	AR
mitochondrial disease	Moderate	AR

Mondo (6): leukocyte adhesion deficiency type II (MONDO:0009953), mitochondrial complex I deficiency, nuclear type 8 (MONDO:0032613), Leigh syndrome (MONDO:0009723), mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), mitochondrial complex I deficiency (MONDO:0100133), (MONDO:0016815)

Orphanet (4): Leukocyte adhesion deficiency (Orphanet:2968), Leukocyte adhesion deficiency type II (Orphanet:99843), Leigh syndrome (Orphanet:506), Isolated complex I deficiency (Orphanet:2609)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000114	Proximal tubulopathy
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000543	Optic disc pallor
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000817	Reduced eye contact
HP:0000819	Diabetes mellitus
HP:0001138	Optic neuropathy
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001639	Hypertrophic cardiomyopathy
HP:0001733	Pancreatitis
HP:0001943	Hypoglycemia
HP:0002013	Vomiting
HP:0002015	Dysphagia
HP:0002093	Respiratory insufficiency
HP:0002151	Increased circulating lactate concentration
HP:0002240	Hepatomegaly

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST000830_15	Body mass index	2.000000e-12
GCST005232_56	Neuroticism	1.000000e-16
GCST006716_13	Alcohol use disorder (total score)	6.000000e-09
GCST006923_11	Loneliness	1.000000e-07
GCST006924_13	Loneliness (MTAG)	1.000000e-08
GCST007293_118	Body fat distribution (arm fat ratio)	3.000000e-08
GCST007293_19	Body fat distribution (arm fat ratio)	2.000000e-10
GCST007293_45	Body fat distribution (arm fat ratio)	5.000000e-14
GCST007294_28	Body fat distribution (trunk fat ratio)	6.000000e-09
GCST007294_9	Body fat distribution (trunk fat ratio)	4.000000e-06
GCST007295_159	Body fat distribution (leg fat ratio)	1.000000e-18
GCST007295_24	Body fat distribution (leg fat ratio)	7.000000e-08
GCST007295_50	Body fat distribution (leg fat ratio)	2.000000e-12
GCST007559_27	Sleep duration (short sleep)	4.000000e-08
GCST007825_4	Alzheimer’s disease or fasting glucose levels (pleiotropy)	3.000000e-16
GCST008103_60	Bipolar disorder	5.000000e-07
GCST008163_345	Height	2.000000e-08
GCST008357_37	Mood instability	9.000000e-14
GCST010002_238	Refractive error	2.000000e-14
GCST010136_2	Fruit consumption	5.000000e-09
GCST010703_36	Brain morphology (MOSTest)	8.000000e-09
GCST010988_417	Adult body size	3.000000e-27
GCST010989_98	Body size at age 10	1.000000e-24

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007660	neuroticism measurement
EFO:0009458	alcohol use disorder measurement
EFO:0007865	loneliness measurement
EFO:0004341	body fat distribution
EFO:0008475	mood instability measurement
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement
EFO:0009819	comparative body size at age 10, self-reported

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
C535755	Congenital disorder of glycosylation, type 2C (supp.)
C537475	Mitochondrial complex I deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363065 (PROTEIN COMPLEX), CHEMBL6067008 (SINGLE PROTEIN)

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

ChEMBL bioactivities

12 potent at pChembl≥5 of 22 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	Kd	2.003	nM	CHEMBL5653589
8.70	ED50	2.003	nM	CHEMBL5653589
6.06	IC50	870	nM	R-(+)-MARMIN-6’-UNDECANOATE
6.04	IC50	920	nM	R-(+)-MARMIN-6’-LINOLEATE
5.63	IC50	2350	nM	R-(+)-MARMIN-6’-LINOLEATE
5.51	IC50	3080	nM	R-(+)-MARMIN-6’-OCTANOATE
5.43	IC50	3670	nM	R-(+)-MARMIN-6’-UNDECANOATE
5.43	IC50	3710	nM	R-(+)-MARMIN-6’-OCTANOATE
5.32	Kd	4772	nM	CHEMBL3752910
5.32	ED50	4772	nM	CHEMBL3752910
5.31	IC50	4900	nM	(+)-9’-ISOVALEROXYLARICIRESINOL
5.04	IC50	9100	nM	(+)-9’-ISOVALEROXYLARICIRESINOL

PubChem BioAssay actives

10 with measured affinity, of 32 total; 6 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	2148854: Binding affinity to human NDUFS3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0020	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] undecanoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	0.8700	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] (9Z,12Z)-octadeca-9,12-dienoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	0.9200	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] octanoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	3.0800	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148854: Binding affinity to human NDUFS3 incubated for 45 mins by Kinobead based pull down assay	kd	4.7724	uM
[(2S,3R,4R)-2-(4-hydroxy-3-methoxyphenyl)-4-[(4-hydroxy-3-methoxyphenyl)methyl]oxolan-3-yl]methyl 3-methylbutanoate	739269: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1,10-phenanthroline-induced HIF1 activation incubated for 30 mins prior to 1,10-phenanthroline-challenge measured after 16 hrs by luciferase reporter assay	ic50	4.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects binding, increases reaction, decreases expression, increases abundance, increases expression	4
bisphenol A	decreases expression, increases expression	3
Arsenic	decreases expression, increases expression, increases abundance	3
Resveratrol	affects cotreatment, increases expression	2
Acetaminophen	affects cotreatment, decreases expression	2
Valproic Acid	affects expression, decreases methylation	2
1-Methyl-4-phenylpyridinium	decreases expression	2
Cyclosporine	decreases expression	2
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression	1
alpha-naphthoflavone	decreases expression, decreases reaction	1
3-methyladenine	decreases expression, decreases reaction	1
chromium hexavalent ion	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
corosolic acid	decreases expression	1
K 7174	decreases expression	1
bisphenol B	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
bromovanin	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	affects expression	1
Atrazine	decreases expression	1
Cisplatin	increases expression	1
Chlorpyrifos	decreases expression, decreases reaction	1
Estradiol	affects binding, increases reaction	1
Furaldehyde	affects cotreatment, increases expression, affects localization	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2353025	Binding	Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation at 30 uM incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	Semisynthetic studies identify mitochondria poisons from botanical dietary supplements–geranyloxycoumarins from Aegle marmelos. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3C6	Abcam HEK293T NDUFS3 KO	Transformed cell line	Female
CVCL_B5KF	HAP1 NDUFS3 (-) 2	Cancer cell line	Male
CVCL_B5KG	HAP1 NDUFS3 (-) 3	Cancer cell line	Male
CVCL_B5KH	HAP1 NDUFS3 (-) 4	Cancer cell line	Male
CVCL_XQ89	HAP1 NDUFS3 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells
NCT03354533	PHASE1/PHASE2	COMPLETED	Study of ORL-1F (L-fucose) in Patients With Leukocyte Adhesion Deficiency Type II