NDUFS7

Summary

NDUFS7 (NADH:ubiquinone oxidoreductase core subunit S7, HGNC:7714) is a protein-coding gene on chromosome 19p13.3, encoding NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial (O75251). 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: 14.3% of cell lines).

This gene encodes a protein that is a subunit of one of the complexes that forms the mitochondrial respiratory chain. This protein is one of over 40 subunits found in complex I, the nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase. This complex functions in the transfer of electrons from NADH to the respiratory chain, and ubiquinone is believed to be the immediate electron acceptor for the enzyme. Mutations in this gene cause Leigh syndrome due to mitochondrial complex I deficiency, a severe neurological disorder that results in bilaterally symmetrical necrotic lesions in subcortical brain regions.

Source: NCBI Gene 374291 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 368 total — 6 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 50
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 14.3% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_024407

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7714
Approved symbol	NDUFS7
Name	NADH:ubiquinone oxidoreductase core subunit S7
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	PSST, FLJ46880, FLJ45860, CI-20
Ensembl gene	ENSG00000115286
Ensembl biotype	protein_coding
OMIM	601825
Entrez	374291

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 13 protein_coding, 10 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000233627, ENST00000313408, ENST00000414651, ENST00000436115, ENST00000534853, ENST00000535382, ENST00000538523, ENST00000538662, ENST00000538929, ENST00000539480, ENST00000539882, ENST00000540530, ENST00000543289, ENST00000545446, ENST00000546172, ENST00000546283, ENST00000591358, ENST00000622587, ENST00000874014, ENST00000874015, ENST00000874016, ENST00000874017, ENST00000874018, ENST00000874019, ENST00000930043, ENST00000930044

RefSeq mRNA: 2 — MANE Select: NM_024407 NM_001363602, NM_024407

CCDS: CCDS12063, CCDS86683

Canonical transcript exons

ENST00000233627 — 8 exons

Exon	Start	End
ENSE00002230106	1383907	1383942
ENSE00003489963	1391119	1391165
ENSE00003507019	1387811	1387847
ENSE00003576835	1390871	1391050
ENSE00003605499	1388833	1388938
ENSE00003646196	1393242	1393330
ENSE00003660932	1388525	1388593
ENSE00003740671	1395391	1395584

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 99.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 52.5946 / max 440.6453, expressed in 1822 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172954	47.4822	1819
172953	5.0930	1715
172955	0.0193	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	99.20	gold quality
apex of heart	UBERON:0002098	99.14	gold quality
gastrocnemius	UBERON:0001388	98.84	gold quality
mucosa of transverse colon	UBERON:0004991	98.72	gold quality
right atrium auricular region	UBERON:0006631	98.71	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.65	gold quality
heart left ventricle	UBERON:0002084	98.51	gold quality
cardiac ventricle	UBERON:0002082	98.34	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.29	gold quality
muscle of leg	UBERON:0001383	98.12	gold quality
left testis	UBERON:0004533	98.10	gold quality
right testis	UBERON:0004534	98.07	gold quality
right frontal lobe	UBERON:0002810	97.98	gold quality
cerebellar hemisphere	UBERON:0002245	97.96	gold quality
cerebellar cortex	UBERON:0002129	97.84	gold quality
right adrenal gland	UBERON:0001233	97.83	gold quality
muscle organ	UBERON:0001630	97.81	gold quality
skeletal muscle organ	UBERON:0014892	97.81	gold quality
adenohypophysis	UBERON:0002196	97.71	gold quality
right adrenal gland cortex	UBERON:0035827	97.67	gold quality
triceps brachii	UBERON:0001509	97.62	gold quality
left adrenal gland	UBERON:0001234	97.58	gold quality
transverse colon	UBERON:0001157	97.56	gold quality
body of stomach	UBERON:0001161	97.55	gold quality
vastus lateralis	UBERON:0001379	97.47	gold quality
left adrenal gland cortex	UBERON:0035825	97.44	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.43	gold quality
cardiac atrium	UBERON:0002081	97.31	gold quality
lower esophagus mucosa	UBERON:0035834	97.24	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.12
E-MTAB-7303	no	1049.05

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

3 targeting NDUFS7, 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-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4736	97.96	65.89	1287

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 14.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

• A patient with Leigh syndrome (LS), born to consanguineous parents, with severe complex I defect and a novel mutation in the NDUFS7 gene subunit. (PMID:17275378)
• Intronic NDUFS7 gene mutation is associated with activation of a cryptic exon and impaired assembly of mitochondrial complex I in a patient with Leigh syndrome (PMID:17604671)
• Both the amount and intrinsic activity of complex I are decreased in inherited complex I deficiency, ehich can be increased by Trolox. (PMID:18435906)
• no active role of NDUFS7 gene in schizophrenia, was found. (PMID:22935918)
• However, similar to another family member, RdmB, it catalyzes the introduction of a hydroxyl group, in the case of NDUFAF5, into Arg-73 in the NDUFS7 subunit of human complex I (PMID:27226634)
• SLC7A11-mediated cystine import protects against NDUFS7 deficiency-induced cell death in HEK293T cells. (PMID:38823363)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufs7	ENSDARG00000074552
mus_musculus	Ndufs7	ENSMUSG00000020153
rattus_norvegicus	Ndufs7	ENSRNOG00000024568
drosophila_melanogaster	ND-20	FBGN0030718
drosophila_melanogaster	ND-20L	FBGN0039669
caenorhabditis_elegans	nduf-7	WBGENE00012376

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial — O75251 (reviewed: O75251)

Alternative names: Complex I-20kD, NADH-ubiquinone oxidoreductase 20 kDa subunit, PSST subunit

All UniProt accessions (6): O75251, F5GXJ1, F5H5N1, F5H736, K7ENU3, Q7LD69

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 of complex I.

Subunit / interactions. Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits. This is a component of the iron-sulfur (IP) fragment of the enzyme.

Subcellular location. Mitochondrion inner membrane.

Post-translational modifications. Hydroxylated at Arg-111 by NDUFAF5 early in the pathway of assembly of complex I, before the formation of the juncture between peripheral and membrane arms.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 3 (MC1DN3) [MIM:618224] 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. MC1DN3 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 [4Fe-4S] cluster.

Similarity. Belongs to the complex I 20 kDa subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
O75251-1	1	yes
O75251-2	2

RefSeq proteins (2): NP_001350531, NP_077718* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006137	NADH_UbQ_OxRdtase-like_20kDa	Domain
IPR006138	NADH_UQ_OxRdtase_20Kd_su	Family

Pfam: PF01058

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (27 total): helix 9, binding site 4, sequence variant 3, turn 3, strand 2, transit peptide 1, chain 1, region of interest 1, compositionally biased region 1, modified residue 1, splice variant 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-O75251-F1	82.93	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 (4): 88; 89; 153; 183

Post-translational modifications (1): 111

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-611105	Respiratory electron transport
R-HSA-6799198	Complex I biogenesis
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism

MSigDB gene sets: 350 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_ATP_BIOSYNTHETIC_PROCESS, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS

GO Biological Process (6): mitochondrial electron transport, NADH to ubiquinone (GO:0006120), aerobic respiration (GO:0009060), electron transport coupled proton transport (GO:0015990), mitochondrial respiratory chain complex I assembly (GO:0032981), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), proton transmembrane transport (GO:1902600)

GO Molecular Function (11): protease binding (GO:0002020), monooxygenase activity (GO:0004497), NADH dehydrogenase (ubiquinone) activity (GO:0008137), oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor (GO:0016655), metal ion binding (GO:0046872), quinone binding (GO:0048038), 4 iron, 4 sulfur cluster binding (GO:0051539), NADH dehydrogenase activity (GO:0003954), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (7): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), neuronal cell body (GO:0043025), respiratory chain complex I (GO:0045271), synaptic membrane (GO:0097060), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Respiratory electron transport	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	2
oxidoreductase activity, acting on NAD(P)H	2
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
cellular respiration	1
energy coupled proton transmembrane transport, against electrochemical gradient	1
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	1
monoatomic cation transmembrane transport	1
enzyme binding	1
oxidoreductase activity	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
cation binding	1
small molecule binding	1
iron-sulfur cluster binding	1
binding	1
catalytic activity	1
metal cluster binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
intracellular organelle lumen	1
somatodendritic compartment	1
cell body	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1
synapse	1
plasma membrane region	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3049 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFS7	NDUFS8	O00217	999
NDUFS7	NDUFS2	O75306	998
NDUFS7	NDUFS3	O75489	998
NDUFS7	NDUFV1	P49821	997
NDUFS7	NDUFS1	P28331	995
NDUFS7	NDUFV2	P19404	991
NDUFS7	NDUFA9	Q16795	968
NDUFS7	MT-ND3	P03897	950
NDUFS7	NDUFS6	O75380	944
NDUFS7	NDUFS4	O43181	933
NDUFS7	MT-ND5	P03915	929
NDUFS7	MT-ND6	P03923	911
NDUFS7	NDUFA11	Q86Y39	891
NDUFS7	MT-ND1	P03886	875
NDUFS7	MT-ND4	P03905	860

IntAct

102 interactions, top by confidence:

A	B	Type	Score
NDUFAF4	NDUFS7	psi-mi:“MI:0914”(association)	0.790
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	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
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFAF1	NDUFS5	psi-mi:“MI:0914”(association)	0.640
NDUFS7	JPH3	psi-mi:“MI:0915”(physical association)	0.560
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFA9	NDUFS8	psi-mi:“MI:0914”(association)	0.530
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFC2	NDUFS4	psi-mi:“MI:0914”(association)	0.530
NDUFB8	NDUFS4	psi-mi:“MI:0914”(association)	0.530
NDUFB5	NDUFS7	psi-mi:“MI:0914”(association)	0.530

BioGRID (470): NDUFS7 (Affinity Capture-MS), NDUFS7 (Affinity Capture-MS), NDUFS7 (Affinity Capture-MS), NDUFS7 (Affinity Capture-MS), SCO1 (Affinity Capture-MS), NDUFAF5 (Affinity Capture-MS), ALDH6A1 (Affinity Capture-MS), NDUFAF4 (Affinity Capture-MS), ETHE1 (Affinity Capture-MS), NDUFAF3 (Affinity Capture-MS), ACAD9 (Affinity Capture-MS), NDUFS7 (Affinity Capture-MS), LONP1 (Affinity Capture-MS), NQO1 (Affinity Capture-MS), NDUFS2 (Affinity Capture-MS)

ESM2 similar proteins: A0QU35, A1T6A5, A3PKI1, A3PWS0, A4WT69, A4X1X5, A8M069, A9GUX6, A9HN98, A9W1N2, B0SZ51, B0ULK5, B1KJU9, B1MPG5, B1ZA45, B3Q6T4, B3Q7N5, B6JGW0, B7KQ65, B8DS03, B8GWV5, B8IUU7, B9KJI0, C0ZYJ9, C1AYM4, C5C0S6, O75251, P0CB83, Q07NM6, Q07QX4, Q0BSK3, Q0MQI0, Q0S449, Q135X5, Q13BH4, Q1BBP4, Q1QL85, Q20Z40, Q215I4, Q2J0F2

Diamond homologs: A0K922, A0LDS6, A1V2L7, A2S458, A2SFM7, A3MIA2, A3N7L8, A3NTA7, A4G643, A4JGC9, A4SXQ2, A5CXF8, A5FX09, A5IHW2, A6SY06, A8EZ83, A8F1C7, A8GN54, A8GRR7, A8GX77, A9AFY8, A9HRU3, A9II02, B0BX73, B0RR99, B1JVP0, B1XUJ9, B1Y828, B1YTQ6, B2FNX8, B2I785, B2JDM7, B2SVL8, B2T2E8, B2U7R0, B3R3W8, B4E5M1, B4SQT5, B5EM21, B5EN70

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NDUFS7	“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 73 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	25	79.6×	2e-41
Respiratory electron transport	25	45.8×	8e-35
Aerobic respiration and respiratory electron transport	24	40.9×	4e-32
Mitochondrial protein degradation	7	15.4×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	19	108.1×	1e-32
proton motive force-driven mitochondrial ATP synthesis	20	83.6×	4e-32
aerobic respiration	20	78.7×	1e-31
mitochondrial respiratory chain complex I assembly	12	78.3×	2e-18

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	13
Uncertain significance	69
Likely benign	216
Benign	33

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
1070144	NC_000019.9:g.(?1387800)(1401485_?)del	Pathogenic
214831	NM_024407.5(NDUFS7):c.2T>C (p.Met1Thr)	Pathogenic
2759429	NM_024407.5(NDUFS7):c.94C>T (p.Gln32Ter)	Pathogenic
2829143	NM_024407.5(NDUFS7):c.267C>A (p.Cys89Ter)	Pathogenic
3242709	NC_000019.9:g.(?1390850)(1391184_?)del	Pathogenic
7682	NM_024407.5(NDUFS7):c.434G>A (p.Arg145His)	Pathogenic
1806253	NM_024407.5(NDUFS7):c.304G>A (p.Asp102Asn)	Likely pathogenic
1982013	NM_024407.5(NDUFS7):c.54-1G>A	Likely pathogenic
2442036	NM_024407.5(NDUFS7):c.537C>A (p.Tyr179Ter)	Likely pathogenic
2725699	NM_024407.5(NDUFS7):c.16+1G>C	Likely pathogenic
2765013	NM_024407.5(NDUFS7):c.229-2A>C	Likely pathogenic
2819120	NM_024407.5(NDUFS7):c.455+2T>C	Likely pathogenic
2840349	NM_024407.5(NDUFS7):c.17-1G>T	Likely pathogenic
2857867	NM_024407.5(NDUFS7):c.123-1G>C	Likely pathogenic
3583495	NM_024407.5(NDUFS7):c.345_354del (p.Gln116fs)	Likely pathogenic
3583496	NM_024407.5(NDUFS7):c.408+1G>C	Likely pathogenic
4278096	NM_024407.5(NDUFS7):c.335C>T (p.Ala112Val)	Likely pathogenic
689475	NM_024407.5(NDUFS7):c.415G>A (p.Asp139Asn)	Likely pathogenic
7683	NM_024407.5(NDUFS7):c.17-1167C>G	Likely pathogenic

SpliceAI

1408 predictions. Top by Δscore:

Variant	Effect	Δscore
19:1388523:A:AG	acceptor_gain	1.0000
19:1388524:G:GG	acceptor_gain	1.0000
19:1388934:GCCGG:G	donor_gain	1.0000
19:1388937:GG:G	donor_gain	1.0000
19:1388937:GGGT:G	donor_loss	1.0000
19:1388938:GG:G	donor_gain	1.0000
19:1388939:G:C	donor_loss	1.0000
19:1388939:G:GG	donor_gain	1.0000
19:1388940:TGA:T	donor_loss	1.0000
19:1388941:GAG:G	donor_loss	1.0000
19:1390870:GA:G	acceptor_gain	1.0000
19:1393240:A:AG	acceptor_gain	1.0000
19:1393241:G:GG	acceptor_gain	1.0000
19:1388519:C:CA	acceptor_gain	0.9900
19:1388520:GGCA:G	acceptor_loss	0.9900
19:1388522:CAGCT:C	acceptor_loss	0.9900
19:1388523:A:T	acceptor_loss	0.9900
19:1388524:GCTCC:G	acceptor_gain	0.9900
19:1388825:T:TA	acceptor_gain	0.9900
19:1388827:T:TA	acceptor_gain	0.9900
19:1388831:A:AG	acceptor_gain	0.9900
19:1388832:G:GA	acceptor_gain	0.9900
19:1388832:GC:G	acceptor_gain	0.9900
19:1388936:CGG:C	donor_gain	0.9900
19:1388937:GGG:G	donor_gain	0.9900
19:1390867:GCAGA:G	acceptor_loss	0.9900
19:1390868:CAG:C	acceptor_gain	0.9900
19:1390868:CAGA:C	acceptor_loss	0.9900
19:1390869:A:AG	acceptor_gain	0.9900
19:1390869:AG:A	acceptor_loss	0.9900

AlphaMissense

1372 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:1390908:G:A	C89Y	0.999
19:1390979:A:C	S113R	0.999
19:1390981:C:A	S113R	0.999
19:1390981:C:G	S113R	0.999
19:1390998:T:A	V119D	0.999
19:1391013:G:T	G124V	0.999
19:1391161:G:T	G151W	0.999
19:1390892:T:C	F84L	0.998
19:1390894:C:A	F84L	0.998
19:1390894:C:G	F84L	0.998
19:1390904:T:C	C88R	0.998
19:1390905:G:A	C88Y	0.998
19:1390909:C:G	C89W	0.998
19:1390917:A:T	E92V	0.998
19:1391010:C:A	A123D	0.998
19:1391012:G:C	G124R	0.998
19:1391013:G:A	G124D	0.998
19:1391019:T:A	L126H	0.998
19:1391153:T:A	V148D	0.998
19:1391156:C:T	S149F	0.998
19:1391161:G:A	G151R	0.998
19:1391161:G:C	G151R	0.998
19:1391162:G:A	G151E	0.998
19:1391162:G:T	G151V	0.998
19:1391164:A:C	S152R	0.998
19:1393242:C:A	S152R	0.998
19:1393242:C:G	S152R	0.998
19:1393244:G:A	C153Y	0.998
19:1395393:T:C	C183R	0.998
19:1395400:C:A	P185H	0.998

dbSNP variants (sampled 300 via entrez): RS1000084904 (19:1390957 C>G,T), RS1000113395 (19:1383458 G>A,C), RS1000123762 (19:1388122 C>T), RS1000607911 (19:1390654 C>A,T), RS1000828588 (19:1386461 G>A), RS1000898558 (19:1382755 C>G), RS1000986155 (19:1382586 G>C), RS1001017239 (19:1386991 G>A), RS1001071634 (19:1394826 C>T), RS1001115473 (19:1382574 G>A), RS1001213349 (19:1385049 C>G), RS1001353374 (19:1382694 T>TC), RS1001643484 (19:1395135 G>C), RS1001803142 (19:1387250 C>T), RS1001856528 (19:1391964 T>A)

Disease associations

OMIM: gene MIM:601825 | disease phenotypes: MIM:256000, MIM:300352, MIM:618224, MIM:252010

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 3	Definitive	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
mitochondrial disease	Definitive	AR
Leigh syndrome	Moderate	AR

Mondo (7): Leigh syndrome (MONDO:0009723), cerebral creatine deficiency syndrome (MONDO:0000456), mitochondrial complex I deficiency, nuclear type 3 (MONDO:0032608), mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), mitochondrial disease (MONDO:0044970), (MONDO:0016815), mitochondrial complex I deficiency (MONDO:0100133)

Orphanet (3): Leigh syndrome (Orphanet:506), Creatine deficiency syndrome (Orphanet:79172), Mitochondrial disease (Orphanet:68380)

HPO phenotypes

50 total (30 of 50 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:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001639	Hypertrophic cardiomyopathy
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0002013	Vomiting
HP:0002071	Abnormality of extrapyramidal motor function

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

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
C537475	Mitochondrial complex I deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363065 (PROTEIN COMPLEX), CHEMBL6067015 (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
8.51	Kd	3.088	nM	CHEMBL3752910
8.51	ED50	3.088	nM	CHEMBL3752910
6.06	IC50	870	nM	R-(+)-MARMIN-6’-UNDECANOATE
6.04	IC50	920	nM	R-(+)-MARMIN-6’-LINOLEATE
5.74	Kd	1814	nM	CHEMBL5653589
5.74	ED50	1814	nM	CHEMBL5653589
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
5.31	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-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148856: Binding affinity to human NDUFS7 incubated for 45 mins by Kinobead based pull down assay	kd	0.0031	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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148856: Binding affinity to human NDUFS7 incubated for 45 mins by Kinobead based pull down assay	kd	1.8140	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
[(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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases expression	3
bisphenol A	decreases methylation, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	decreases expression	1
arsenite	affects binding, increases reaction	1
methylparaben	decreases expression	1
perfluorooctanoic acid	decreases expression	1
coenzyme Q10	increases expression	1
ochratoxin A	increases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
manganese(III)-tetrakis(4-benzoic acid)porphyrin	increases expression	1
corosolic acid	decreases expression	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
Acetylcysteine	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases abundance, increases expression	1
Cadmium	decreases expression	1
Isoniazid	decreases expression	1
Ivermectin	increases expression	1
Malathion	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Niclosamide	decreases expression	1
Phthalic Acids	increases methylation	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tunicamycin	increases expression	1
Valproic Acid	affects expression	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

1 cell lines: 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_EQ44	5175	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
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)
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
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