NDUFV1

Summary

NDUFV1 (NADH:ubiquinone oxidoreductase core subunit V1, HGNC:7716) is a protein-coding gene on chromosome 11q13.2, encoding NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial (P49821). 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: 20.9% of cell lines).

The mitochondrial respiratory chain provides energy to cells via oxidative phosphorylation and consists of four membrane-bound electron-transporting protein complexes (I-IV) and an ATP synthase (complex V). This gene encodes a 51 kDa subunit of the NADH:ubiquinone oxidoreductase complex I; a large complex with at least 45 nuclear and mitochondrial encoded subunits that liberates electrons from NADH and channels them to ubiquinone. This subunit carries the NADH-binding site as well as flavin mononucleotide (FMN)- and Fe-S-biding sites. Defects in complex I are a common cause of mitochondrial dysfunction; a syndrome that occurs in approximately 1 in 10,000 live births. Mitochondrial complex I deficiency is linked to myopathies, encephalomyopathies, and neurodegenerative disorders such as Parkinson’s disease and Leigh syndrome. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 4723 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 434 total — 24 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 51
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 20.9% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_007103

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7716
Approved symbol	NDUFV1
Name	NADH:ubiquinone oxidoreductase core subunit V1
Location	11q13.2
Locus type	gene with protein product
Status	Approved
Aliases	CI-51K
Ensembl gene	ENSG00000167792
Ensembl biotype	protein_coding
OMIM	161015
Entrez	4723

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 26 protein_coding, 10 retained_intron, 4 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000322776, ENST00000415352, ENST00000524838, ENST00000524876, ENST00000525086, ENST00000526138, ENST00000526169, ENST00000526770, ENST00000527355, ENST00000527923, ENST00000528314, ENST00000528328, ENST00000528377, ENST00000528548, ENST00000529867, ENST00000529927, ENST00000530014, ENST00000530103, ENST00000530638, ENST00000531250, ENST00000532244, ENST00000532260, ENST00000532303, ENST00000532343, ENST00000533075, ENST00000533919, ENST00000534139, ENST00000534352, ENST00000647561, ENST00000879257, ENST00000879258, ENST00000879259, ENST00000879260, ENST00000879261, ENST00000926237, ENST00000926238, ENST00000926239, ENST00000926240, ENST00000926241, ENST00000926242, ENST00000926243, ENST00000964389, ENST00000964390

RefSeq mRNA: 2 — MANE Select: NM_007103 NM_001166102, NM_007103

CCDS: CCDS53669, CCDS8173

Canonical transcript exons

ENST00000322776 — 10 exons

Exon	Start	End
ENSE00001771732	67606936	67607076
ENSE00003464641	67609452	67609635
ENSE00003501994	67611403	67611569
ENSE00003504134	67611897	67611978
ENSE00003515070	67608552	67608722
ENSE00003532227	67612120	67612265
ENSE00003561301	67610381	67610570
ENSE00003566313	67608396	67608478
ENSE00003571913	67610995	67611207
ENSE00003836838	67612372	67612554

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 145.8863 / max 1840.9329, expressed in 1828 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115502	145.6468	1828
115501	0.2396	63

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.44	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.20	gold quality
metanephros cortex	UBERON:0010533	99.18	gold quality
cerebellar hemisphere	UBERON:0002245	99.15	gold quality
heart left ventricle	UBERON:0002084	99.13	gold quality
cerebellar cortex	UBERON:0002129	99.12	gold quality
right atrium auricular region	UBERON:0006631	99.11	gold quality
mucosa of transverse colon	UBERON:0004991	99.09	gold quality
cardiac ventricle	UBERON:0002082	99.08	gold quality
right uterine tube	UBERON:0001302	99.04	gold quality
right lobe of thyroid gland	UBERON:0001119	99.02	gold quality
cardiac atrium	UBERON:0002081	99.02	gold quality
gastrocnemius	UBERON:0001388	98.94	gold quality
right frontal lobe	UBERON:0002810	98.92	gold quality
transverse colon	UBERON:0001157	98.91	gold quality
left lobe of thyroid gland	UBERON:0001120	98.89	gold quality
muscle of leg	UBERON:0001383	98.82	gold quality
heart	UBERON:0000948	98.79	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.77	gold quality
cerebellum	UBERON:0002037	98.75	gold quality
left ovary	UBERON:0002119	98.74	gold quality
right ovary	UBERON:0002118	98.73	gold quality
body of stomach	UBERON:0001161	98.70	gold quality
prefrontal cortex	UBERON:0000451	98.67	gold quality
skin of leg	UBERON:0001511	98.66	gold quality
right adrenal gland	UBERON:0001233	98.64	gold quality
right adrenal gland cortex	UBERON:0035827	98.63	gold quality
skin of abdomen	UBERON:0001416	98.57	gold quality
thyroid gland	UBERON:0002046	98.57	gold quality
granulocyte	CL:0000094	98.56	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

Upstream regulators (CollecTRI, top): CREB1, NCOR1, SP1

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 20.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• Sp1 was abnormally expressed in schizophrenia and its mRNA alteration pattern paralleled that of NDUFV1 and NDUFV2 in schizophrenic patients. (PMID:17786189)
• Mutations in the NDUFV1 gene is linked to a delayed mitochondrial network recovery in OXPHOS disorders. (PMID:20153825)
• significant negative-correlation between left ventricular end-diastolic dimension and NDUFV1 production in dilated cardiomyopathy (PMID:20930427)
• observed 2 consanguinous siblings with early-onset encephalopathy, medulla, brainstem and mesencephalon lesions and death before 8 months of age, caused by a complex I deficiency; identified a missense mutation in the NDUFV1 gene; the mutation, p.Arg386His, affects a highly conserved residue (PMID:21696386)
• study describes clinical, radiological, biochemical and molecular data of 6 patients with Leigh syndrome with novel mutations in NDUFV1 and NDUFS2; 2 siblings were homozygous for previously undescribed R386C mutation in NDUFV1 (PMID:23266820)
• The results affirm that NDUFV1 mutations are causative of the phenotype in two siblings affected by a diffuse leukodystrophy. (PMID:23562761)
• small number of putative de novo variants were transmitted from BAP parents to their ASD offspring, and evidence emerged for a rare duplication CNV at 11p13.3 harboring two putative developmental/neuropsychiatric susceptibility gene(s), GSTP1 and NDUFV1. (PMID:25432440)
• The presented clinical courses of NDUFV1 and NDUFS1 mutation-based complex I deficiencies are characterized by leukoencephalopathy or early death and expand the already heterogeneous phenotypic spectrum. (PMID:25615419)
• we have used a yeast model system to study the molecular consequences of 16 single amino acid substitutions, classified as pathogenic, in the NDUFV1 subunit of complex I (PMID:26345448)
• Mutations in the ND6, NDUFV1 or ACAD9 genes are responsible for the mitochondrial complex I deficiency. (PMID:29348607)
• Biallelic missense variants in NDUFV1 were identified in two cases of mitochondrial complex I deficiency. (PMID:29976978)
• Intracellular CYTL1, a novel tumor suppressor, stabilizes NDUFV1 to inhibit metabolic reprogramming in breast cancer. (PMID:35115484)
• Compound heterozygous mutations of NDUFV1 identified in a child with mitochondrial complex I deficiency. (PMID:35482246)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufv1	ENSDARG00000036438
mus_musculus	Ndufv1	ENSMUSG00000037916
rattus_norvegicus	Ndufv1	ENSRNOG00000018117
drosophila_melanogaster	ND-51	FBGN0031771
drosophila_melanogaster	ND-51L2	FBGN0034007
drosophila_melanogaster	ND-51L1	FBGN0034251
caenorhabditis_elegans		WBGENE00003831

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial — P49821 (reviewed: P49821)

Alternative names: Complex I-51kD, NADH dehydrogenase flavoprotein 1, NADH-ubiquinone oxidoreductase 51 kDa subunit

All UniProt accessions (14): B4DE93, E5KNH5, E9PJL9, E9PLC6, E9PMX3, E9PPD6, P49821, E9PPE0, E9PPR0, E9PPS5, E9PQP1, G3V0I5, H0YD04, H0YE81

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. Part of the peripheral arm of the enzyme, where the electrons from NADH are accepted by flavin mononucleotide (FMN) and then passed along a chain of iron-sulfur clusters by electron tunnelling to the final acceptor ubiquinone. Contains FMN, which is the initial electron acceptor as well as one iron-sulfur cluster.

Subunit / interactions. Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits. This is a component of the flavoprotein-sulfur (FP) fragment of the enzyme. Interacts with RAB5IF.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 4 (MC1DN4) [MIM:618225] 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. MC1DN4 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

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

Similarity. Belongs to the complex I 51 kDa subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
P49821-1	1	yes
P49821-2	2

RefSeq proteins (2): NP_001159574, NP_009034* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001949	NADH-UbQ_OxRdtase_51kDa_CS	Conserved_site
IPR011537	NADH-UbQ_OxRdtase_suF	Family
IPR011538	Nuo51_FMN-bd	Domain
IPR019575	Nuop51_4Fe4S-bd	Domain
IPR037207	Nuop51_4Fe4S-bd_sf	Homologous_superfamily
IPR037225	Nuo51_FMN-bd_sf	Homologous_superfamily
IPR050837	ComplexI_51kDa_subunit	Family
IPR054765	SLBB_dom	Domain

Pfam: PF01512, PF10589, PF22461

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (64 total): helix 21, strand 14, binding site 6, turn 6, modified residue 5, sequence variant 5, sequence conflict 4, transit peptide 1, chain 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-P49821-F1	93.47	0.90

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 (6): 87–96; 199–247; 379; 382; 385; 425

Post-translational modifications (5): 104, 257, 375, 81, 81

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-611105	Respiratory electron transport
R-HSA-6799198	Complex I biogenesis
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 309 (showing top): MORF_MTA1, MODULE_93, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, MODULE_77, MORF_HDAC1, MORF_UBE2N, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, MORF_HDAC2, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, chr11q13, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT

GO Biological Process (5): mitochondrial electron transport, NADH to ubiquinone (GO:0006120), aerobic respiration (GO:0009060), mitochondrial ATP synthesis coupled electron transport (GO:0042775), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), proton transmembrane transport (GO:1902600)

GO Molecular Function (8): NADH dehydrogenase (ubiquinone) activity (GO:0008137), FMN binding (GO:0010181), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), NAD binding (GO:0051287), 4 iron, 4 sulfur cluster binding (GO:0051539), protein binding (GO:0005515), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), respiratory chain complex I (GO:0045271), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	2
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
cellular respiration	1
ATP synthesis coupled electron transport	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	1
monoatomic cation transmembrane transport	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
ribonucleotide binding	1
anion binding	1
catalytic activity	1
cation binding	1
adenyl nucleotide binding	1
iron-sulfur cluster binding	1
binding	1
metal cluster binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3356 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFV1	NDUFV2	P19404	999
NDUFV1	NDUFS1	P28331	999
NDUFV1	NDUFS7	O75251	997
NDUFV1	NDUFS3	O75489	997
NDUFV1	NDUFS8	O00217	997
NDUFV1	NDUFS2	O75306	996
NDUFV1	NDUFV3	P56181	984
NDUFV1	NDUFA2	O43678	981
NDUFV1	NDUFS4	O43181	978
NDUFV1	NDUFS6	O75380	971
NDUFV1	NDUFA6	P56556	929
NDUFV1	NDUFA9	Q16795	921
NDUFV1	NDUFA12	Q9UI09	919
NDUFV1	MT-ND5	P03915	893
NDUFV1	MT-ND6	P03923	887

IntAct

191 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
NDUFV2	NDUFS2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NDUFV1	NDUFV3	psi-mi:“MI:0915”(physical association)	0.670
NDUFS6	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
NDUFV1	CYSRT1	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	NDUFV1	psi-mi:“MI:0915”(physical association)	0.560
MNDA	NDUFV1	psi-mi:“MI:0915”(physical association)	0.560
PSMA3	NDUFV1	psi-mi:“MI:0915”(physical association)	0.560
PSMB1	NDUFV1	psi-mi:“MI:0915”(physical association)	0.560
PSMD5	NDUFV1	psi-mi:“MI:0915”(physical association)	0.560
RBBP6	NDUFV1	psi-mi:“MI:0915”(physical association)	0.560
VDAC2	NDUFV1	psi-mi:“MI:0915”(physical association)	0.560
BTRC	NDUFV1	psi-mi:“MI:0915”(physical association)	0.560
COPS2	NDUFV1	psi-mi:“MI:0915”(physical association)	0.560
OPTN	NDUFV1	psi-mi:“MI:0915”(physical association)	0.560
TBC1D22A	NDUFV1	psi-mi:“MI:0915”(physical association)	0.560
SPAG8	NDUFV1	psi-mi:“MI:0915”(physical association)	0.560
FBXO25	NDUFV1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (435): NDUFV1 (Affinity Capture-MS), NDUFV1 (Affinity Capture-MS), NDUFV1 (Two-hybrid), COX5A (Co-fractionation), EEF2 (Co-fractionation), MRPL45 (Co-fractionation), NDUFS1 (Co-fractionation), NDUFV1 (Co-fractionation), NDUFV1 (Co-fractionation), NDUFV1 (Co-fractionation), NDUFV1 (Co-fractionation), NDUFV1 (Co-fractionation), NDUFV1 (Co-fractionation), NDUFV1 (Co-fractionation), NDUFV1 (Co-fractionation)

ESM2 similar proteins: A0Q0E8, A2BQQ9, A3PCI2, A6URV4, A8EXI1, A8F0M0, A8G4F2, A8GM77, A8GQT6, A8GYE0, A9BAQ7, B0TLI4, B1GYS7, B1KKJ2, O07948, O52682, O66841, P22317, P25708, P29913, P31979, P33901, P49821, P56912, P56913, P57256, P65568, P9WIV6, P9WIV7, Q0MQI4, Q0MQI5, Q0MQI6, Q1RHA0, Q31BA3, Q46507, Q492E0, Q4UKA6, Q54I90, Q56222, Q68XY3

Diamond homologs: A8EXI1, A8F0M0, A8GM77, A8GQT6, A8GYE0, O07948, O52682, O66841, O94500, P22317, P24917, P25708, P29913, P31979, P33901, P49821, P56912, P56913, P57256, P65568, P9WIV6, P9WIV7, Q0MQI4, Q0MQI5, Q0MQI6, Q1RHA0, Q46507, Q4UKA6, Q54I90, Q56222, Q68XY3, Q89AU2, Q8HXQ9, Q8K9Y3, Q91YT0, Q92406, Q92JB2, Q9FNN5, Q9I0J7, Q9XAQ9

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
SP1	“up-regulates quantity by expression”	NDUFV1	“transcriptional regulation”
STOML2	“up-regulates activity”	NDUFV1
NDUFV1	“form complex”	“NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I”	binding
CDK1	“up-regulates activity”	NDUFV1	phosphorylation
CyclinB/CDK1	“up-regulates activity”	NDUFV1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 130 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	43.5×	5e-33
Respiratory electron transport	26	26.1×	3e-28
Aerobic respiration and respiratory electron transport	27	25.2×	7e-29
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	5	12.5×	3e-03
Mitochondrial protein import	7	12.4×	1e-04
Mitochondrial protein degradation	8	9.6×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	20	61.8×	2e-29
proton motive force-driven mitochondrial ATP synthesis	24	54.5×	2e-33
aerobic respiration	23	49.1×	5e-31
mitochondrial respiratory chain complex I assembly	11	39.0×	6e-13

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	26
Uncertain significance	127
Likely benign	172
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1299402	NM_007103.4(NDUFV1):c.797dup (p.Arg267fs)	Pathogenic
1323338	NM_007103.4(NDUFV1):c.336T>G (p.Tyr112Ter)	Pathogenic
14057	NM_007103.4(NDUFV1):c.175C>T (p.Arg59Ter)	Pathogenic
14059	NM_007103.4(NDUFV1):c.640G>A (p.Glu214Lys)	Pathogenic
2063984	NM_007103.4(NDUFV1):c.201dup (p.Ile68fs)	Pathogenic
214863	NM_007103.4(NDUFV1):c.617G>A (p.Cys206Tyr)	Pathogenic
2247547	NM_007103.4(NDUFV1):c.153G>A (p.Trp51Ter)	Pathogenic
2637752	NM_007103.4(NDUFV1):c.499del (p.Ser167fs)	Pathogenic
2694566	NM_007103.4(NDUFV1):c.283del (p.Thr95fs)	Pathogenic
2732786	NM_007103.4(NDUFV1):c.422_425del (p.Gly141fs)	Pathogenic
2759622	NM_007103.4(NDUFV1):c.186G>A (p.Trp62Ter)	Pathogenic
2773065	NM_007103.4(NDUFV1):c.459del (p.Ala154fs)	Pathogenic
280782	NM_007103.4(NDUFV1):c.53_54del (p.Val18fs)	Pathogenic
2830437	NM_007103.4(NDUFV1):c.338del (p.Leu113fs)	Pathogenic
2841726	NM_007103.4(NDUFV1):c.449del (p.Gly150fs)	Pathogenic
2860312	NM_007103.4(NDUFV1):c.950_951dup (p.Ile318Ter)	Pathogenic
2900118	NM_007103.4(NDUFV1):c.289_298del (p.Leu97fs)	Pathogenic
2907412	NM_007103.4(NDUFV1):c.914-8_947del	Pathogenic
2982558	NM_007103.4(NDUFV1):c.655A>T (p.Lys219Ter)	Pathogenic
2992614	NM_007103.4(NDUFV1):c.419_420insTCCTCACAAGCTGA (p.Glu140fs)	Pathogenic
3244773	NC_000011.9:g.(?67366019)(67374523_?)del	Pathogenic
4688270	NC_000011.9:g.(?_67374406)_67374523del	Pathogenic
4735212	NM_007103.4(NDUFV1):c.30G>A (p.Trp10Ter)	Pathogenic
632170	NM_007103.4(NDUFV1):c.753_756del (p.Pro252fs)	Pathogenic
1324787	NM_007103.4(NDUFV1):c.151_152del (p.Trp51fs)	Likely pathogenic
1332824	NM_007103.4(NDUFV1):c.380A>G (p.Asp127Gly)	Likely pathogenic
1348541	NM_007103.4(NDUFV1):c.510+1G>T	Likely pathogenic
2137165	NM_007103.4(NDUFV1):c.156-2A>G	Likely pathogenic
214848	NM_007103.4(NDUFV1):c.116A>G (p.Asp39Gly)	Likely pathogenic
214856	NM_007103.4(NDUFV1):c.479G>A (p.Gly160Glu)	Likely pathogenic

SpliceAI

1679 predictions. Top by Δscore:

Variant	Effect	Δscore
11:67608390:CCCTA:C	acceptor_loss	1.0000
11:67608391:CCTA:C	acceptor_loss	1.0000
11:67608392:CTAGA:C	acceptor_loss	1.0000
11:67608393:TAGAC:T	acceptor_loss	1.0000
11:67608394:A:AG	acceptor_gain	1.0000
11:67608394:AGACA:A	acceptor_loss	1.0000
11:67608395:G:GA	acceptor_gain	1.0000
11:67608395:GACA:G	acceptor_gain	1.0000
11:67608476:G:GT	donor_gain	1.0000
11:67608476:GAGG:G	donor_loss	1.0000
11:67608477:AGGTG:A	donor_loss	1.0000
11:67608478:GGTGA:G	donor_loss	1.0000
11:67608479:G:C	donor_loss	1.0000
11:67608480:T:G	donor_loss	1.0000
11:67608550:A:AG	acceptor_gain	1.0000
11:67608550:AGGCT:A	acceptor_gain	1.0000
11:67608551:G:GG	acceptor_gain	1.0000
11:67608551:GGCTG:G	acceptor_gain	1.0000
11:67608702:GAA:G	donor_gain	1.0000
11:67608704:A:AG	donor_gain	1.0000
11:67609447:TGCA:T	acceptor_loss	1.0000
11:67609448:GCAG:G	acceptor_loss	1.0000
11:67609449:CA:C	acceptor_loss	1.0000
11:67609450:A:AG	acceptor_gain	1.0000
11:67609451:G:GA	acceptor_gain	1.0000
11:67609634:AG:A	donor_loss	1.0000
11:67610375:CTGCA:C	acceptor_loss	1.0000
11:67610376:TGCAG:T	acceptor_loss	1.0000
11:67610377:GCAGG:G	acceptor_loss	1.0000
11:67610378:CA:C	acceptor_loss	1.0000

AlphaMissense

2999 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:67608671:G:A	G92D	1.000
11:67608673:T:C	F93L	1.000
11:67608674:T:C	F93S	1.000
11:67608674:T:G	F93C	1.000
11:67608675:C:A	F93L	1.000
11:67608675:C:G	F93L	1.000
11:67608688:A:G	K98E	1.000
11:67608690:G:C	K98N	1.000
11:67608690:G:T	K98N	1.000
11:67609473:C:A	N116K	1.000
11:67609473:C:G	N116K	1.000
11:67610487:G:A	C206Y	1.000
11:67610488:T:G	C206W	1.000
11:67610490:G:A	G207E	1.000
11:67610496:A:T	E209V	1.000
11:67610555:T:C	F229L	1.000
11:67610557:C:A	F229L	1.000
11:67610557:C:G	F229L	1.000
11:67611556:T:A	V356D	1.000
11:67611933:T:C	F373L	1.000
11:67611935:C:A	F373L	1.000
11:67611935:C:G	F373L	1.000
11:67611952:G:A	C379Y	1.000
11:67611960:T:C	C382R	1.000
11:67612230:T:C	C425R	1.000
11:67612231:G:A	C425Y	1.000
11:67612232:T:G	C425W	1.000
11:67608653:G:C	R86T	0.999
11:67608653:G:T	R86M	0.999
11:67608654:G:C	R86S	0.999

dbSNP variants (sampled 300 via entrez): RS1000116638 (11:67605018 T>C,G), RS1001447274 (11:67605896 G>A,C), RS1001680298 (11:67611309 A>C,G), RS1001983248 (11:67605540 C>A), RS1002015734 (11:67610035 A>C), RS1002503480 (11:67610037 A>G), RS1002522564 (11:67611938 T>A), RS1002583022 (11:67606988 C>G), RS1002651968 (11:67606820 C>G), RS1002692970 (11:67612510 A>G), RS1003205399 (11:67606606 A>G), RS1003659217 (11:67605283 A>T), RS1003937765 (11:67610867 A>T), RS1003971210 (11:67607710 G>A,T), RS1004006732 (11:67610149 C>G,T)

Disease associations

OMIM: gene MIM:161015 | disease phenotypes: MIM:252010, MIM:618225, MIM:256000, MIM:618120

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 4	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
Leigh syndrome	Definitive	AR
mitochondrial disease	Definitive	AR

Mondo (8): mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), mitochondrial complex I deficiency, nuclear type 4 (MONDO:0032609), Leigh syndrome (MONDO:0009723), mitochondrial complex I deficiency (MONDO:0100133), mitochondrial complex V (ATP synthase) deficiency, nuclear type 5 (MONDO:0020858), mitochondrial complex I deficiency, nuclear type (MONDO:0100223), mitochondrial disease (MONDO:0044970), (MONDO:0016815)

Orphanet (3): Leigh syndrome (Orphanet:506), Isolated complex I deficiency (Orphanet:2609), Mitochondrial disease (Orphanet:68380)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000114	Proximal tubulopathy
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000543	Optic disc pallor
HP:0000602	Ophthalmoplegia
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:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001336	Myoclonus
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:0002093	Respiratory insufficiency

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), CHEMBL6066881 (SINGLE PROTEIN)

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

ChEMBL bioactivities

8 potent at pChembl≥5 of 20 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
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
5.31	IC50	4900	nM	(+)-9’-ISOVALEROXYLARICIRESINOL
5.04	IC50	9100	nM	(+)-9’-ISOVALEROXYLARICIRESINOL

PubChem BioAssay actives

8 with measured affinity, of 30 total; 4 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
[(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
[(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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, increases abundance, increases expression	5
Arsenic	decreases expression, increases abundance, increases expression, increases methylation	3
Valproic Acid	affects expression, increases expression	3
cobaltous chloride	decreases expression	2
Acetaminophen	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Cadmium	decreases reaction, increases abundance, increases palmitoylation, decreases expression	2
Paraquat	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Aflatoxin B1	increases methylation	2
bisphenol F	increases expression	1
bisphenol A	increases expression	1
beta-lapachone	decreases expression, increases expression	1
tanshinone	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
benzo(e)pyrene	decreases methylation	1
acipimox	decreases expression	1
arsenic trichloride	decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression	1
Temozolomide	decreases expression	1
Air Pollutants, Occupational	affects expression	1
Coumestrol	increases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Estradiol	increases expression	1
Fluorouracil	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

2 cell lines: 1 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B3C7	Abcam HEK293T NDUFV1 KO	Transformed cell line	Female
CVCL_ZA82	UOMi002-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

112 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