NDUFAF4

Summary

NDUFAF4 (NADH:ubiquinone oxidoreductase complex assembly factor 4, HGNC:21034) is a protein-coding gene on chromosome 6q16.1, encoding NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 4 (Q9P032). Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I). It is a selective cancer dependency (DepMap: 21.9% of cell lines).

NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. This gene encodes a complex I assembly factor. Mutations in this gene are a cause of mitochondrial complex I deficiency.

Source: NCBI Gene 29078 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +3 more curated relationships
• Clinical variants (ClinVar): 121 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 55
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 21.9% of screened cell lines
• MANE Select transcript: NM_014165

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21034
Approved symbol	NDUFAF4
Name	NADH:ubiquinone oxidoreductase complex assembly factor 4
Location	6q16.1
Locus type	gene with protein product
Status	Approved
Aliases	HSPC125, bA22L21.1, My013, HRPAP20
Ensembl gene	ENSG00000123545
Ensembl biotype	protein_coding
OMIM	611776
Entrez	29078

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000316149, ENST00000478382, ENST00000489477, ENST00000872119, ENST00000926051, ENST00000926052, ENST00000926053

RefSeq mRNA: 1 — MANE Select: NM_014165 NM_014165

CCDS: CCDS5037

Canonical transcript exons

ENST00000316149 — 3 exons

Exon	Start	End
ENSE00001449354	96897666	96897891
ENSE00001670496	96889315	96891391
ENSE00003621908	96896744	96896847

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 97.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.1752 / max 444.9620, expressed in 1802 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74777	32.6570	1799
74776	0.2803	113
74775	0.2380	93

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	97.37	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.84	gold quality
heart right ventricle	UBERON:0002080	95.79	gold quality
heart left ventricle	UBERON:0002084	95.33	gold quality
cardiac ventricle	UBERON:0002082	95.26	gold quality
endothelial cell	CL:0000115	95.01	gold quality
mucosa of transverse colon	UBERON:0004991	94.15	gold quality
biceps brachii	UBERON:0001507	94.06	gold quality
heart	UBERON:0000948	93.99	gold quality
right atrium auricular region	UBERON:0006631	93.92	gold quality
apex of heart	UBERON:0002098	93.74	gold quality
left ventricle myocardium	UBERON:0006566	93.65	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.57	gold quality
cardiac atrium	UBERON:0002081	93.49	gold quality
gastrocnemius	UBERON:0001388	93.45	gold quality
cerebellar vermis	UBERON:0004720	93.33	gold quality
cortical plate	UBERON:0005343	93.00	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.97	gold quality
muscle of leg	UBERON:0001383	92.94	gold quality
substantia nigra pars compacta	UBERON:0001965	92.86	gold quality
myocardium	UBERON:0002349	92.66	gold quality
oocyte	CL:0000023	92.56	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.56	gold quality
skeletal muscle organ	UBERON:0014892	92.48	gold quality
muscle organ	UBERON:0001630	92.47	gold quality
prefrontal cortex	UBERON:0000451	92.28	gold quality
middle temporal gyrus	UBERON:0002771	91.96	gold quality
rectum	UBERON:0001052	91.84	gold quality
superior vestibular nucleus	UBERON:0007227	91.41	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.35	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

89 targeting NDUFAF4, 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-4262	100.00	73.26	3931
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-652-5P	99.91	67.49	505
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-130B-5P	99.83	68.50	1888

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 21.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• observations suggest that HRPAP20 may be an important regulator of breast tumor cell invasion by a CaM-mediated mechanism that leads to increased MMP-9 secretion (PMID:17001319)
• HRPAP20 and TIMELESS as promising markers of tamoxifen resistance in women with ER alpha-positive breast tumors. (PMID:17909269)
• Homozygosity mapping of 5 patients from a consanguineous family with infantile mitochondrial encephalomyopathy resulted in the identification of a missense mutation in a conserved residue of the C6ORF66. (PMID:18179882)
• Specific lack of complex I was detected in thyroid cancers expressing less than 5% of the amount in surrounding non-cancerous tissue. (PMID:19352385)
• Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease. (PMID:19463981)
• A homozygous missense NDUFAF4 variant was identified in a complex I-deficient patient with Leigh syndrome. (PMID:28853723)
• Complex I deficiency, due to NDUFAF4 mutations, causes severe mitochondrial dysfunction and is associated to early death and dysmorphia. (PMID:32949790)
• A genetic variant in gene NDUFAF4 confers the risk of non-small cell lung cancer by perturbing hsa-miR-215 binding. (PMID:37787384)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufaf4	ENSDARG00000077859
mus_musculus	Ndufaf4	ENSMUSG00000028261
drosophila_melanogaster	CG11722	FBGN0037777
caenorhabditis_elegans		WBGENE00007113

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 4 — Q9P032 (reviewed: Q9P032)

Alternative names: Hormone-regulated proliferation-associated protein of 20 kDa

All UniProt accessions (1): Q9P032

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I). May be involved in cell proliferation and survival of hormone-dependent tumor cells. May be a regulator of breast tumor cell invasion.

Subunit / interactions. Binds calmodulin. Interacts with NDUFAF3. (Microbial infection) Interacts with the vesicular stomatitis virus matrix protein/M; the interaction inhibits viral propagation.

Subcellular location. Mitochondrion. Membrane.

Post-translational modifications. Phosphorylated on serine. Prolactin stimulate serine phosphorylation.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 15 (MC1DN15) [MIM:618237] 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. MC1DN15 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Induction. Expression is low in quiescent cells and is induced in exponentially proliferating cultures. Expression is also induced when prolactin is added to stationary cells. Induced by dietary differentiating agents such as butyrate and retinoic acid.

Similarity. Belongs to the NDUFAF4 family.

RefSeq proteins (1): NP_054884* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009622	NDUFAF4	Family

Pfam: PF06784

UniProt features (7 total): sequence variant 2, initiator methionine 1, chain 1, modified residue 1, lipid moiety-binding region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P032-F1	83.37	0.45

Functional residue map

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

Post-translational modifications (2): 35, 2

Mutagenesis-validated functional residues (1):

Position	Phenotype
73	reduces interaction with calmodulin. does not promote mmp-9 secretion.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

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

MSigDB gene sets: 294 (showing top): GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, WEI_MYCN_TARGETS_WITH_E_BOX, MODULE_205, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_DEFENSE_RESPONSE_TO_VIRUS, DODD_NASOPHARYNGEAL_CARCINOMA_UP, HAN_SATB1_TARGETS_DN, BERENJENO_TRANSFORMED_BY_RHOA_UP, GOBP_RESPONSE_TO_VIRUS, GOCC_ORGANELLE_INNER_MEMBRANE, STEIN_ESRRA_TARGETS_UP

GO Biological Process (3): mitochondrial respiratory chain complex I assembly (GO:0032981), defense response to virus (GO:0051607), NADH dehydrogenase complex assembly (GO:0010257)

GO Molecular Function (2): calmodulin binding (GO:0005516), protein binding (GO:0005515)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), cytosol (GO:0005829), mitochondrial membrane (GO:0031966), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
cellular anatomical structure	2
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
defense response	1
response to virus	1
protein-containing complex assembly	1
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

1394 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFAF4	NDUFAF3	Q9BU61	977
NDUFAF4	NDUFAF2	Q8N183	892
NDUFAF4	NDUFAF5	Q5TEU4	885
NDUFAF4	NDUFS2	O75306	879
NDUFAF4	FOXRED1	Q96CU9	858
NDUFAF4	NDUFAF6	Q330K2	857
NDUFAF4	NDUFS3	O75489	855
NDUFAF4	NUBPL	Q8TB37	851
NDUFAF4	NDUFS7	O75251	845
NDUFAF4	NDUFS8	O00217	836
NDUFAF4	NDUFAF1	Q9Y375	822
NDUFAF4	NDUFA11	Q86Y39	765
NDUFAF4	NDUFV2	P19404	739
NDUFAF4	MT-ND1	P03886	739
NDUFAF4	NDUFS6	O75380	736

IntAct

116 interactions, top by confidence:

A	B	Type	Score
NDUFAF3	NDUFAF4	psi-mi:“MI:0915”(physical association)	0.890
NDUFAF4	NDUFS7	psi-mi:“MI:0914”(association)	0.790
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
NDUFAF4	NDUFAF3	psi-mi:“MI:0915”(physical association)	0.720
NDUFAF3	NDUFAF4	psi-mi:“MI:0915”(physical association)	0.720
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFAF4	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFAF4	GRN	psi-mi:“MI:0915”(physical association)	0.560
NDUFAF4	WFS1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (241): NDUFAF4 (Two-hybrid), NDUFAF4 (Affinity Capture-MS), NDUFAF4 (Affinity Capture-MS), NDUFAF4 (Affinity Capture-MS), NDUFAF4 (Affinity Capture-MS), NDUFAF4 (Affinity Capture-MS), NDUFAF4 (Affinity Capture-MS), NDUFAF4 (Affinity Capture-MS), NDUFAF4 (Affinity Capture-MS), NDUFAF4 (Affinity Capture-MS), NDUFAF4 (Affinity Capture-MS), NDUFAF3 (Affinity Capture-MS), NDUFAF4 (Affinity Capture-MS), NDUFAF4 (Affinity Capture-MS), NDUFS7 (Affinity Capture-MS)

ESM2 similar proteins: A4FUH5, A5DY61, A7S1A4, A9UMQ3, B0BN56, B2RYU8, B3MGU5, B3N8S9, B4GDB3, B4HRL4, B4KPG8, B4MRE7, B4NXN5, B4P2P8, B4QFP7, B5DZ31, B5FYC7, C5MJD6, O43325, O74370, O74988, P13618, P34748, P36527, P82925, P87127, Q08230, Q09261, Q20716, Q21939, Q290P4, Q498P2, Q4V5I9, Q5R4R9, Q61733, Q6BY05, Q6FT82, Q7JWG9, Q8WTJ4, Q92665

Diamond homologs: A4FUH5, Q5R4R9, Q9D1H6, Q9NQR8, Q9P032, Q9VH39

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 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	14	29.0×	9e-15
Respiratory electron transport	12	14.3×	7e-09
Aerobic respiration and respiratory electron transport	12	13.3×	1e-08
Mitochondrial protein degradation	6	8.6×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial respiratory chain complex I assembly	12	53.0×	2e-15
mitochondrial electron transport, NADH to ubiquinone	9	34.7×	2e-09
proton motive force-driven mitochondrial ATP synthesis	9	25.5×	2e-08
aerobic respiration	9	24.0×	3e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	66
Likely benign	23
Benign	18

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
790	NM_014165.4(NDUFAF4):c.194T>C (p.Leu65Pro)	Pathogenic
3776782	NM_014165.4(NDUFAF4):c.19C>A (p.Arg7Ser)	Likely pathogenic

SpliceAI

564 predictions. Top by Δscore:

Variant	Effect	Δscore
6:96896071:G:C	donor_gain	1.0000
6:96896740:TTAC:T	donor_loss	1.0000
6:96896741:TA:T	donor_loss	1.0000
6:96896780:CACAT:C	donor_gain	1.0000
6:96896844:TAGA:T	acceptor_gain	1.0000
6:96896845:AGA:A	acceptor_gain	1.0000
6:96896846:GA:G	acceptor_gain	1.0000
6:96896848:C:CC	acceptor_gain	1.0000
6:96897664:A:AC	donor_gain	1.0000
6:96897665:C:CC	donor_gain	1.0000
6:96897665:CGA:C	donor_gain	1.0000
6:96897672:T:C	donor_gain	1.0000
6:96891390:ACC:A	acceptor_loss	0.9900
6:96891392:C:CC	acceptor_gain	0.9900
6:96891393:T:A	acceptor_loss	0.9900
6:96896015:T:TA	donor_gain	0.9900
6:96896082:A:AC	donor_gain	0.9900
6:96896083:C:CC	donor_gain	0.9900
6:96896784:T:C	donor_gain	0.9900
6:96896843:ATAGA:A	acceptor_gain	0.9900
6:96897377:C:A	donor_gain	0.9900
6:96897658:CCA:C	donor_gain	0.9900
6:96897665:CG:C	donor_gain	0.9900
6:96897665:CGACT:C	donor_gain	0.9900
6:96897726:T:TA	donor_gain	0.9900
6:96891387:TTTAC:T	acceptor_gain	0.9800
6:96891388:TTAC:T	acceptor_gain	0.9800
6:96891389:TAC:T	acceptor_gain	0.9800
6:96897281:A:AC	donor_gain	0.9800
6:96897282:C:CC	donor_gain	0.9800

AlphaMissense

1158 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:96891277:C:G	A119P	0.923
6:96896775:A:T	V70D	0.875
6:96896790:A:G	L65P	0.875
6:96891155:A:C	F159L	0.871
6:96891155:A:T	F159L	0.871
6:96891157:A:G	F159L	0.871
6:96891164:A:C	F156L	0.864
6:96891164:A:T	F156L	0.864
6:96891166:A:G	F156L	0.864
6:96897713:G:T	A30D	0.861
6:96891267:A:G	L122P	0.839
6:96891235:A:G	W133R	0.836
6:96891235:A:T	W133R	0.836
6:96897750:C:G	A18P	0.825
6:96897752:C:G	R17P	0.820
6:96897703:G:C	H33Q	0.817
6:96897703:G:T	H33Q	0.817
6:96896781:A:T	V68E	0.812
6:96897798:C:G	G2R	0.811
6:96897798:C:T	G2R	0.811
6:96891264:A:G	L123P	0.810
6:96891177:A:G	L152P	0.803
6:96897743:C:G	R20P	0.800
6:96896790:A:T	L65Q	0.798
6:96891207:T:G	Y142S	0.796
6:96891208:A:C	Y142D	0.795
6:96891201:A:G	L144S	0.790
6:96897737:A:C	I22S	0.790
6:96891177:A:C	L152R	0.784
6:96891297:C:A	G112V	0.776

dbSNP variants (sampled 300 via entrez): RS1000301452 (6:96894479 G>C,T), RS1000461534 (6:96890482 T>C), RS1000683149 (6:96895707 C>T), RS1000993834 (6:96889099 T>C), RS1001539333 (6:96894876 T>A,C), RS1001568260 (6:96893700 C>A,T), RS1002206053 (6:96899706 A>G), RS1002760066 (6:96898346 G>A), RS1003082633 (6:96898096 C>G), RS1003544056 (6:96897754 G>A,C,T), RS1003704810 (6:96896938 CTTTTT>C,CTTTTTT), RS1003726185 (6:96889075 A>C), RS1003765230 (6:96897198 T>G), RS1003983399 (6:96897541 A>C,T), RS1004576916 (6:96889686 T>A,C)

Disease associations

OMIM: gene MIM:611776 | disease phenotypes: MIM:252010, MIM:618237

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 15	Strong	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	Limited	AR
mitochondrial disease	Definitive	AR

Mondo (3): mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), mitochondrial complex I deficiency, nuclear type 15 (MONDO:0032620), mitochondrial complex I deficiency (MONDO:0100133)

Orphanet (1): Isolated complex I deficiency (Orphanet:2609)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000114	Proximal tubulopathy
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000543	Optic disc pallor
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000737	Irritability
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:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001371	Flexion contracture
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001639	Hypertrophic cardiomyopathy
HP:0001942	Metabolic acidosis

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537475	Mitochondrial complex I deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363065 (PROTEIN COMPLEX), CHEMBL6067528 (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
8.82	Kd	1.498	nM	CHEMBL3752910
8.82	ED50	1.498	nM	CHEMBL3752910
6.06	IC50	870	nM	R-(+)-MARMIN-6’-UNDECANOATE
6.04	IC50	920	nM	R-(+)-MARMIN-6’-LINOLEATE
5.74	Kd	1823	nM	CHEMBL5653589
5.74	ED50	1823	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	2148844: Binding affinity to human NDUFAF4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0015	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	2148844: Binding affinity to human NDUFAF4 incubated for 45 mins by Kinobead based pull down assay	kd	1.8235	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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
arsenite	affects binding, increases reaction, increases methylation	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
trichostatin A	affects expression	1
methylparaben	decreases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
bisphenol S	increases expression	1
jinfukang	decreases 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	decreases expression	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Cadmium	increases abundance, increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	increases O-linked glycosylation, decreases activity	1
Estradiol	increases expression	1
Fluorouracil	affects expression	1
Formaldehyde	decreases expression	1
Manganese	increases expression, affects cotreatment, increases abundance	1
Methyl Methanesulfonate	decreases 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 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2D9	HAP1 NDUFAF4 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

1 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)