MT-ND1

Summary

MT-ND1 (mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1, HGNC:7455) is a protein-coding gene on chromosome mitochondria, encoding NADH-ubiquinone oxidoreductase chain 1 (P03886). 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.

Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial inner membrane. Part of respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer’s disease; Parkinson’s disease; and multiple sclerosis.

Source: NCBI Gene 4535 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +5 more curated relationships
• Clinical variants (ClinVar): 190 total — 2 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 178
• Druggable target: yes

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7455
Approved symbol	MT-ND1
Name	mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1
Location	mitochondria
Locus type	gene with protein product
Status	Approved
Aliases	ND1, NAD1
Ensembl gene	ENSG00000198888
Ensembl biotype	protein_coding
OMIM	516000
Entrez	4535

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000361390

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

ENST00000361390 — 1 exons

Exon	Start	End
ENSE00001435714	3307	4262

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1304.1036 / max 216825.2414, expressed in 1827 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194845	1304.1036	1827

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adipose tissue	UBERON:0001013	99.99	gold quality
gastrocnemius	UBERON:0001388	99.99	gold quality
frontal cortex	UBERON:0001870	99.99	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.99	gold quality
superior frontal gyrus	UBERON:0002661	99.99	gold quality
right frontal lobe	UBERON:0002810	99.99	gold quality
left testis	UBERON:0004533	99.99	gold quality
right testis	UBERON:0004534	99.99	gold quality
metanephros cortex	UBERON:0010533	99.99	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.99	gold quality
zone of skin	UBERON:0000014	99.98	gold quality
prefrontal cortex	UBERON:0000451	99.98	gold quality
transverse colon	UBERON:0001157	99.98	gold quality
fundus of stomach	UBERON:0001160	99.98	gold quality
body of stomach	UBERON:0001161	99.98	gold quality
mucosa of stomach	UBERON:0001199	99.98	gold quality
cortex of kidney	UBERON:0001225	99.98	gold quality
right adrenal gland	UBERON:0001233	99.98	gold quality
left adrenal gland	UBERON:0001234	99.98	gold quality
right uterine tube	UBERON:0001302	99.98	gold quality
left uterine tube	UBERON:0001303	99.98	gold quality
skin of abdomen	UBERON:0001416	99.98	gold quality
skin of leg	UBERON:0001511	99.98	gold quality
temporal lobe	UBERON:0001871	99.98	gold quality
caudate nucleus	UBERON:0001873	99.98	gold quality
putamen	UBERON:0001874	99.98	gold quality
amygdala	UBERON:0001876	99.98	gold quality
nucleus accumbens	UBERON:0001882	99.98	gold quality
hypothalamus	UBERON:0001898	99.98	gold quality
Ammon’s horn	UBERON:0001954	99.98	gold quality

Single-cell (SCXA)

Detected in 63 experiment(s), a significant marker in 26.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	35977.20
E-GEOD-124263	yes	22047.49
E-CURD-88	yes	16536.28
E-MTAB-8207	yes	15714.68
E-GEOD-137537	yes	15315.44
E-HCAD-6	yes	14665.30
E-MTAB-6505	yes	14288.36
E-MTAB-7008	yes	13836.97
E-MTAB-9435	yes	13539.34
E-MTAB-8884	yes	13342.12
E-GEOD-180759	yes	12467.75
E-CURD-98	yes	12178.06
E-MTAB-10885	yes	12019.76
E-MTAB-7407	yes	11048.08
E-CURD-46	yes	9696.13

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• Novel mitochondrial DNA mutations in Parkinson’s disease. we report novel homoplasmic base changes. We were unable to detect heteroplasmic base changes. (PMID:12111463)
• presence of the A3796G mutation increases the risk of developing adult-onset dystonia. (PMID:12756609)
• The expression of MTDN1 was studied in blood platelets during aging. There was increased genetic transcription. (PMID:14759509)
• Both mRNA and protein levels of the 24-kDa and 51-kDa subunits of complex I were significantly decreased in the prefrontal cortex, but increased in the ventral parietooccipital cortices of schizophrenia patients compared with normal control subjects. (PMID:15038995)
• three novel mutations causing MELAS syndrome (PMID:15466014)
• A novel mitochondrial DNA (mtDNA) transition (3733G–>A) inducing the E143 K amino acid change at a very conserved site of the ND1 was identified in a family with six maternally related individuals with Leber’s hereditary optic neuropathy (LHON) (PMID:15505787)
• This study has found alterations in two AD patients: one had two already known mtDNA modifications (3197 T-C and 3338 T-C) and the other a novel transition (3199 T-C). (PMID:15860916)
• The mutations G3460A and G11778A in the mitochondrial genes MTND1 and MTND4, known to be causative for LHON. (PMID:16137960)
• results suggest that the mutations of T3394C and A14693G may contribute to genetic predisposition to type 2 diabetes mellitus, with the T16189C variant being associated with insulin resistance (PMID:16414144)
• mtDNA C3310T mutation in NADH dehydrogenase 1 may be a pathogenic mutation of maternally inherited type 2 diabetes mellitus and hypertrophic cardiomyopathy in the proband and the family. (PMID:16828917)
• Therefore, the tRNA(Glu) A14693G mutation may have a potential modifier role in the phenotypic manifestation of the primary LHON-associated G3460A mutation in this Chinese family. (PMID:17434142)
• Mutation in ND1 protein is associated with non-arteritic anterior ischemic optic neuropathy (PMID:17454741)
• the 3697G>A/ND1 mitochondrial DNA mutation causes the LHON and spastic dystonia phenotype in the same family (PMID:17562939)
• Point mutation occurred in mtDNA might be involved in pathogenesis of multiple sclerosis. (PMID:17619138)
• suggested the involvement of other modifier factors in the pathogenesis of hypertension associated with this ND1 T3308C mutation (PMID:18194667)
• The cause of the observed association between resting metabolic rate and the ND1 polymorphism is not related to in vitro mitochondrial function. (PMID:18239645)
• A novel G3337A ND1 mutation related to cardiomyopathy co-segregates with tRNALeu(CUN) A12308G and tRNAThr C15946T mutations. (PMID:18502698)
• study investigated 2 children with complex I deficiency in muscle mitochondria; 2 DE NOVO mutations in MTND1 were found; a novel heteroplasmic G3890A mutation, R195Q in patient 1; a heteroplasmic G3481A mutation, E59K in patient 2 (PMID:18504678)
• consisted of forcing mRNAs from nuclearly-encoded ND1 and ND4 genes to localize to the mitochondrial surface (PMID:18513491)
• The 3380G>A mutation shows very good evidence of pathogenicity as it is heteroplasmic, undetectable in controls, alters a highly conserved amino acid, and is more abundant in ragged-red than in normal muscle fibers. (PMID:18590963)
• Carriage of the mitochondrial 4216C-allele increases the risk for infectious complications and death after severe trauma. (PMID:19276764)
• Leber’s hereditary optic neuropathy is associated with mitochondrial ND1 T3394C mutation in four Chinese families. (PMID:19324017)
• After adjustment for full-thickness burn size, inhalation injury, age, and sex, carriage of the ND1 4216C allele was associated with complicated sepsis, relative to carriers of the T allele. (PMID:19487983)
• This current observations provide further support for a pathogenic role of m.3635G>A in ND1 in patients with Leber hereditary optic neuropathy. (PMID:19527690)
• the clinical and genetic characterization of a Chinese Leber’s hereditary optic neuropathy family carrying an ND1/C4171A mutation was reported. (PMID:19555656)
• The 3316 G–>A mutation in mitochondrial ND1 gene might be related to the down-regulated expression of mitochondrial protein and the diabetes mellitus pathogenesis. (PMID:20137661)
• T3866C mutation in ND1 is associated with Leber’s hereditary optic neuropathy and limbs abnormity claudication. (PMID:20176558)
• NADH dehydrogenase domain activity of NDH-1 with either one or both mutations was markedly decreased suggesting that m.4216T>C and m.3866T>C may have an effect on the structural integrity of complex I. (PMID:20197120)
• Substitutions of a highly conserved Met31 in ND1 caused by rare mitochondrial single nucleotide polymorphisms (mtSNP) A3397G and T3398C were identified from two left ventricular noncompaction patients. (PMID:20211276)
• these results suggest that the MT-ND1 and MT-ND5 genes are mutational hotspots for Chinese families with suspected LHON lacking the common primary mutations. (PMID:20643099)
• Three mutations in the Mitochondrial Subunit ND1 gene from primary colorectal tumour tissues were likely to alter the structure and function of the ND1 protein (PMID:21329181)
• It is concluded that left ventricular hypertrabeculation/noncompaction may be associated with the known homoplasmic m.3308T>C mutation in the ND1 gene. (PMID:21625124)
• the antitumorigenic and antimetastatic effects of high loads of MTND1 m.3571insC, following tumors complex I disassembly, define a novel threshold-regulated class of cancer genes (PMID:21852384)
• In all, m.3376G>A perturbs ubiquinone binding, a phenomenon found in LHON, and decreases the activity of fully assembled complex I as in MELAS. (PMID:22079202)
• Novel ND1 mutations responsible for maternally inherited nonsyndromic hearing loss (PMID:22241583)
• Studies indicate that NADH dehydrogenase subunit 1 (ND1) nucleotide 3394 T > C (Y30H) has been associated with Leber hereditary optic neuropathy and it reduces complex I activity and cellular respiration. (PMID:22517755)
• These data suggest that the four early Complex I assembly factors have non-redundant functions in the assembly of a module that docks and stabilizes newly synthesized ND1. (PMID:22653752)
• A statistically significant association of the T4216C mutation in ND1 (p < 0.05) between patients suffering recurrent pregnancy loss and controls, which are 30% and 11%, respectively. (PMID:23464625)
• BRN2 is a higher level regulator than ASCL1 and ND1 and BRN2 might be involved in aggressiveness of small cell lung cancer. (PMID:23530560)
• Novel mutations m.3959G>A and m.3995A>G in mitochondrial gene MT-ND1 associated with MELAS. (PMID:23834081)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mt-nd1	ENSDARG00000063895
mus_musculus	mt-Nd1	ENSMUSG00000064341
rattus_norvegicus	Mt-nd1	ENSRNOG00000030644
drosophila_melanogaster	mt:ND1	FBGN0013679
caenorhabditis_elegans		WBGENE00010959

Protein

Protein identifiers

NADH-ubiquinone oxidoreductase chain 1 — P03886 (reviewed: P03886)

Alternative names: NADH dehydrogenase subunit 1

All UniProt accessions (2): P03886, U5Z754

UniProt curated annotations — full annotation on UniProt →

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

Subunit / interactions. Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Leber hereditary optic neuropathy (LHON) [MIM:535000] A maternally inherited form of Leber hereditary optic neuropathy, a mitochondrial disease resulting in bilateral painless loss of central vision due to selective degeneration of the retinal ganglion cells and their axons. The disorder shows incomplete penetrance and male predominance. Cardiac conduction defects and neurological defects have also been described in some LHON patients. LHON results from primary mitochondrial DNA mutations affecting the respiratory chain complexes. The disease is caused by variants affecting the gene represented in this entry. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome (MELAS) [MIM:540000] Genetically heterogeneous disorder, characterized by episodic vomiting, seizures, and recurrent cerebral insults resembling strokes and causing hemiparesis, hemianopsia, or cortical blindness. The disease is caused by variants affecting the gene represented in this entry. Alzheimer disease mitochondrial (AD-MT) [MIM:502500] Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Type 2 diabetes mellitus (T2D) [MIM:125853] A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. The gene represented in this entry may be involved in disease pathogenesis.

Similarity. Belongs to the complex I subunit 1 family.

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001694	NADH_UbQ_OxRdtase_su1/FPO	Family
IPR018086	NADH_UbQ_OxRdtase_su1_CS	Conserved_site

Pfam: PF00146

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (25 total): sequence variant 15, transmembrane region 8, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9I4I	ELECTRON MICROSCOPY	2.63
9TI4	ELECTRON MICROSCOPY	2.66
9CWT	ELECTRON MICROSCOPY	3.44
5XTC	ELECTRON MICROSCOPY	3.7
5XTD	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P03886-F1	91.83	0.80

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5419276	Mitochondrial translation termination
R-HSA-611105	Respiratory electron transport
R-HSA-6799198	Complex I biogenesis
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 449 (showing top): GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TGACCTY_ERR1_Q2, 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_RESPONSE_TO_OXYGEN_LEVELS, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_BIOSYNTHETIC_PROCESS

GO Biological Process (8): response to hypoxia (GO:0001666), mitochondrial electron transport, NADH to ubiquinone (GO:0006120), aerobic respiration (GO:0009060), response to xenobiotic stimulus (GO:0009410), mitochondrial respiratory chain complex I assembly (GO:0032981), response to hydroperoxide (GO:0033194), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), proton transmembrane transport (GO:1902600)

GO Molecular Function (3): NADH dehydrogenase (ubiquinone) activity (GO:0008137), NADH dehydrogenase activity (GO:0003954), protein binding (GO:0005515)

GO Cellular Component (7): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), dendrite (GO:0030425), mitochondrial membrane (GO:0031966), neuronal cell body (GO:0043025), respiratory chain complex I (GO:0045271), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	2
response to stress	1
response to decreased oxygen levels	1
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
cellular respiration	1
response to chemical	1
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
response to oxidative stress	1
response to oxygen-containing compound	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
oxidoreductase activity, acting on NAD(P)H	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
neuron projection	1
dendritic tree	1
mitochondrial envelope	1
organelle membrane	1
somatodendritic compartment	1
cell body	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3347 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MT-ND1	MT-ND2	P03891	999
MT-ND1	MT-ND3	P03897	999
MT-ND1	MT-ND4L	P03901	999
MT-ND1	MT-ND4	P03905	999
MT-ND1	MT-ND5	P03915	998
MT-ND1	MT-ND6	P03923	997
MT-ND1	MT-ATP6	P00846	956
MT-ND1	MT-CYB	P00156	952
MT-ND1	MT-CO1	P00395	939
MT-ND1	MT-ATP8	P03928	889
MT-ND1	PTGS1	P23219	880
MT-ND1	MT-CO3	P00414	876
MT-ND1	NDUFS7	O75251	875
MT-ND1	NDUFS2	O75306	870
MT-ND1	NDUFA1	O15239	850

IntAct

86 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
KLK5	DENND11	psi-mi:“MI:0914”(association)	0.640
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFAF1	NDUFS5	psi-mi:“MI:0914”(association)	0.640
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
BTN2A1	POTEF	psi-mi:“MI:0914”(association)	0.530
VSIG4	TCAF2	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
NDUFA8	NDUFS8	psi-mi:“MI:0914”(association)	0.530
ECSIT	NDUFS8	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
NDUFV2	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFS5	NDUFS4	psi-mi:“MI:0914”(association)	0.530
DNAJC30	NDUFS8	psi-mi:“MI:0914”(association)	0.530
APLNR	SLC33A1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
NDUFA9	NDUFS8	psi-mi:“MI:0914”(association)	0.530

BioGRID (104): ND1 (Affinity Capture-MS), ND1 (Affinity Capture-MS), ND1 (Affinity Capture-MS), ND1 (Affinity Capture-MS), ND1 (Affinity Capture-MS), ND1 (Affinity Capture-MS), ND1 (Affinity Capture-MS), ND1 (Affinity Capture-MS), ND1 (Affinity Capture-MS), ND1 (Affinity Capture-MS), ND1 (Affinity Capture-MS), ND1 (Affinity Capture-MS), ND1 (Affinity Capture-MS), ND1 (Co-fractionation), ND1 (Co-fractionation)

ESM2 similar proteins: O03850, O78693, O78694, O78695, O78696, O78697, O78698, O78701, O78702, O78703, O78711, O79427, P03886, P03887, P03888, P03889, P24967, P24968, P41296, P41304, P48652, P92475, P92690, Q53AV2, Q6EMT1, Q70Y22, Q70Y23, Q70Y26, Q70Y28, Q70Y30, Q8M867, Q8M873, Q8M880, Q8M881, Q8M888, Q8M889, Q8M891, Q8M892, Q8M893, Q8M899

Diamond homologs: B0FWD8, O03850, O21069, O21325, O47479, O48358, O63623, O78679, O78693, O78694, O78695, O78696, O78697, O78698, O78699, O78700, O78701, O78702, O78703, O78704, O78705, O78706, O78707, O78709, O78710, O78711, O78712, O78714, O78715, O78747, O79427, O79546, O79874, O80003, P03886, P03887, P03888, P03889, P03890, P07710

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MT-ND1	“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 82 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	65.7×	9e-39
Respiratory electron transport	22	33.2×	1e-26
Aerobic respiration and respiratory electron transport	22	30.9×	5e-26
Mitochondrial protein degradation	6	10.9×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	19	89.6×	3e-31
proton motive force-driven mitochondrial ATP synthesis	21	72.8×	5e-32
aerobic respiration	21	68.5×	1e-31
mitochondrial respiratory chain complex I assembly	11	59.5×	3e-15
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	5	14.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	9
Uncertain significance	79
Likely benign	37
Benign	48

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
3255386	NC_012920.1(MT-ND1):m.3457G>A	Pathogenic
9722	NC_012920.1(MT-ND1):m.3460G>A	Pathogenic
155881	NC_012920.1(MT-ND1):m.3890G>A	Likely pathogenic
223247	NC_012920.1(MT-TL1):m.3291T>C	Likely pathogenic
3390858	NC_012920.1(MT-ND1):m.3922G>T	Likely pathogenic
3774391	NC_012920.1(MT-ND1):m.3688G>A	Likely pathogenic
65518	NC_012920.1(MT-ND1):m.3635G>A	Likely pathogenic
692374	NC_012920.1(MT-ND1):m.3571del	Likely pathogenic
800504	NC_012920.1(MT-ND1):m.3761C>A	Likely pathogenic
9731	NC_012920.1(MT-ND1):m.3902_3908inv	Likely pathogenic
9733	NC_012920.1(MT-ND1):m.3697G>A	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1981 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
M:3859:T:C	W185R	0.997
M:3937:T:C	F211L	0.995
M:3939:C:A	F211L	0.995
M:3939:C:G	F211L	0.995
M:3898:T:C	F198L	0.994
M:3900:C:A	F198L	0.994
M:3900:C:G	F198L	0.994
M:3964:T:C	F220L	0.994
M:3966:C:A	F220L	0.994
M:3966:C:G	F220L	0.994
M:3890:G:C	R195P	0.993
M:3664:G:T	G120W	0.992
M:3562:T:C	W86R	0.991
M:3634:A:C	S110R	0.991
M:3667:T:C	W121R	0.991
M:3734:A:T	E143V	0.991
M:4174:T:C	W290R	0.991
M:3841:T:C	W179R	0.990
M:4120:T:C	W272R	0.990
M:3380:G:C	R25P	0.989
M:4114:T:C	F270L	0.988
M:4116:C:A	F270L	0.988
M:4116:C:G	F270L	0.988
M:3698:G:A	G131D	0.986
M:4030:T:C	F242L	0.986
M:4032:C:A	F242L	0.986
M:4032:C:G	F242L	0.986
M:3665:G:A	G120E	0.985
M:3720:A:C	Q138H	0.985
M:3720:A:T	Q138H	0.985

dbSNP variants (sampled 300 via entrez): RS1057516055 (MT:1661 A>G), RS1057516056 (MT:1655 A>G), RS1057516057 (MT:3275 C>A,G,T), RS1057516058 (MT:3624 A>C,G), RS1057516059 (MT:4664 C>T), RS1057520067 (MT:4472 T>C), RS1057520173 (MT:3169 C>T), RS1057520201 (MT:4132 G>A), RS111033322 (MT:1406 T>C), RS111033325 (MT:1393 G>A), RS111033326 (MT:1462 G>A,T), RS111033354 (MT:1310 C>T), RS111033356 (MT:1420 T>C), RS111033357 (MT:1391 T>C), RS111033358 (MT:1382 A>C)

Disease associations

OMIM: gene MIM:516000 | disease phenotypes: MIM:256000, MIM:540000, MIM:500008, MIM:500001, MIM:535000, MIM:500009, MIM:221745, MIM:580000, MIM:168600

GenCC curated gene-disease

Disease	Classification	Inheritance
Leber hereditary optic neuropathy	Definitive	Mitochondrial
maternally-inherited Leigh syndrome	Supportive	Mitochondrial
mitochondrial complex I deficiency	Supportive	Autosomal recessive
MELAS syndrome	Supportive	Mitochondrial

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	MT
Leigh syndrome	Definitive	MT

Mondo (22): Leigh syndrome (MONDO:0009723), mitochondrial disease (MONDO:0044970), MELAS syndrome (MONDO:0010789), optic atrophy (MONDO:0003608), mitochondrial non-syndromic sensorineural hearing loss (MONDO:0010779), mitochondrial complex I deficiency (MONDO:0100133), Leber optic atrophy and dystonia (MONDO:0010772), Leber hereditary optic neuropathy (MONDO:0010788), optic nerve disorder (MONDO:0002135), mitochondrial myopathy with reversible cytochrome C oxidase deficiency (MONDO:0010780), intellectual disability (MONDO:0001071), ptosis (MONDO:0000728), restrictive cardiomyopathy (MONDO:0005201), hearing loss, sensorineural, autosomal-mitochondrial type (MONDO:0009090), deafness, aminoglycoside-induced (MONDO:0010799)

Orphanet (15): Leigh syndrome (Orphanet:506), Mitochondrial disease (Orphanet:68380), MELAS (Orphanet:550), Rare mitochondrial non-syndromic sensorineural deafness (Orphanet:90641), Isolated complex I deficiency (Orphanet:2609), Leber hereditary optic neuropathy (Orphanet:104), Leber plus disease (Orphanet:99718), Mitochondrial myopathy with reversible cytochrome C oxidase deficiency (Orphanet:254864), Mitochondrial non-syndromic sensorineural deafness with susceptibility to aminoglycoside exposure (Orphanet:168609), Restrictive cardiomyopathy (Orphanet:217632), Rare genetic deafness (Orphanet:96210), Early-onset autosomal dominant Alzheimer disease (Orphanet:1020), Hereditary late-onset Parkinson disease (Orphanet:411602), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Alzheimer disease (Orphanet:238616)

HPO phenotypes

178 total (30 of 178 shown, HPO-id order):

HPO	Term
HP:0000044	Hypogonadotropic hypogonadism
HP:0000091	Abnormal renal tubule morphology
HP:0000093	Proteinuria
HP:0000097	Focal segmental glomerulosclerosis
HP:0000112	Nephropathy
HP:0000114	Proximal tubulopathy
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000408	Progressive sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000519	Developmental cataract
HP:0000529	Progressive visual loss
HP:0000543	Optic disc pallor
HP:0000551	Color vision defect
HP:0000572	Visual loss
HP:0000576	Centrocecal scotoma
HP:0000580	Pigmentary retinopathy
HP:0000590	Progressive external ophthalmoplegia
HP:0000597	Ophthalmoparesis
HP:0000602	Ophthalmoplegia
HP:0000603	Central scotoma
HP:0000618	Blindness
HP:0000622	Blurred vision
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000709	Psychosis

GWAS associations

0 associations (top):

MeSH disease descriptors (16)

Descriptor	Name	Tree numbers
D000544	Alzheimer Disease	C10.228.140.380.100; C10.574.945.249; F03.615.400.100
D001763	Blepharoptosis	C11.338.204
D002313	Cardiomyopathy, Restrictive	C14.280.238.160
D020821	Dystonic Disorders	C10.228.662.300
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
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
D017241	MELAS Syndrome	C05.651.460.620.520; C10.228.140.163.100.535; C10.228.140.300.275.500; C10.668.491.500.500.500; C14.907.253.329.500; C16.320.565.189.535; C18.452.132.100.535; C18.452.648.189.535; C18.452.660.560.620.520
D008881	Migraine Disorders	C10.228.140.546.399.750
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D029242	Optic Atrophy, Hereditary, Leber	C10.292.700.225.500.400; C10.574.500.662.400; C11.270.564.400; C11.640.451.451.400; C16.320.290.564.400; C16.320.400.630.400; C18.452.660.670
D009901	Optic Nerve Diseases	C10.292.700; C11.640
C564013	Deafness, Aminoglycoside-Induced (supp.)
C565637	Deafness, Sensorineural, Autosomal-Mitochondrial Type (supp.)
C536024	Marsden syndrome (supp.)
C536035	Maternally Inherited Leigh Syndrome (supp.)
C537475	Mitochondrial complex I deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111 (SINGLE PROTEIN), CHEMBL2363065 (PROTEIN COMPLEX)

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1603218569	Toxicity	3	aminoglycoside antibacterials	Ototoxicity
rs267606617	Toxicity	3	isepamicin	Ototoxicity
rs267606619	Toxicity	3	micronomicin	Ototoxicity

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs267606619	MT-ND1, MT-RNR1	1A	102.75	6	streptomycin;gentamicin;micronomicin;tobramycin;kanamycin;aminoglycoside antibacterials
rs267606617	MT-ND1, MT-RNR1	1A	108.50	8	streptomycin;gentamicin;kanamycin;amikacin;tobramycin;isepamicin;aminoglycoside antibacterials;neomycin
rs1603218569	MT-ND1, MT-RNR1	3	0.25	1	aminoglycoside antibacterials

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.51	Kd	306.3	nM	CHEMBL5653589
6.51	ED50	306.3	nM	CHEMBL5653589
6.06	IC50	870	nM	R-(+)-MARMIN-6’-UNDECANOATE
6.04	IC50	920	nM	R-(+)-MARMIN-6’-LINOLEATE
5.63	IC50	2350	nM	R-(+)-MARMIN-6’-LINOLEATE
5.51	IC50	3080	nM	R-(+)-MARMIN-6’-OCTANOATE
5.43	IC50	3670	nM	R-(+)-MARMIN-6’-UNDECANOATE
5.43	IC50	3710	nM	R-(+)-MARMIN-6’-OCTANOATE
5.31	IC50	4900	nM	(+)-9’-ISOVALEROXYLARICIRESINOL
5.04	IC50	9100	nM	(+)-9’-ISOVALEROXYLARICIRESINOL

PubChem BioAssay actives

9 with measured affinity, of 30 total; 5 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148795: Binding affinity to human MT-ND1 incubated for 45 mins by Kinobead based pull down assay	kd	0.3063	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] undecanoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	0.8700	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] (9Z,12Z)-octadeca-9,12-dienoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	0.9200	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] octanoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	3.0800	uM
[(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

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

Chemical	Actions (top 5)	PubMed papers
1-Methyl-4-phenylpyridinium	decreases reaction, decreases expression, increases expression, affects binding	4
Air Pollutants	decreases expression, increases abundance	3
Hydrogen Peroxide	affects cotreatment, affects reaction, decreases expression, decreases reaction	3
fucoxanthin	increases expression, decreases expression, decreases reaction	2
enniatins	decreases expression	2
Atrazine	decreases expression	2
Cadmium	affects expression, increases abundance, decreases expression, affects reaction	2
Paraquat	decreases response to substance, increases expression	2
Rotenone	decreases expression, decreases reaction, increases activity, decreases response to substance	2
Tunicamycin	decreases expression	2
Cadmium Chloride	affects expression, increases abundance, decreases expression, affects reaction	2
bisphenol A	decreases expression	1
tris(2-butoxyethyl) phosphate	increases abundance, increases expression	1
sulforaphane	increases expression	1
sodium arsenite	increases expression	1
3-methyladenine	decreases expression, decreases reaction	1
tris(chloroethyl)phosphate	increases abundance, increases expression	1
1-methyl-4-phenyl-2,3-dihydropyridinium	decreases expression	1
1’,2’-dihydrorotenone	affects binding, decreases reaction	1
epigallocatechin gallate	affects cotreatment, affects reaction, decreases expression, decreases reaction	1
monomethylpropion	increases expression	1
gallocatechol	affects cotreatment, affects reaction, decreases expression, decreases reaction	1
bullatacin	increases activity, increases reaction, increases response to substance	1
epicatechin gallate	affects cotreatment, affects reaction, decreases expression, decreases reaction	1
sarpogrelate	decreases expression, decreases reaction, increases reaction	1
chromium hexavalent ion	decreases expression, decreases reaction	1
4-phenylbutyric acid	decreases reaction, decreases expression	1
BMS-986094	decreases expression	1
MitoTEMPO	decreases expression	1
2-(2’-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid	decreases expression, decreases reaction	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
CHEMBL5651837	Binding	Binding affinity to human MT-ND1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_9916	XTC.UC1	Cancer cell line	Female
CVCL_C1SF	AHMUi001-A	Induced pluripotent stem cell	Male
CVCL_JE93	GM11605	Transformed cell line	Female
CVCL_YD66	FINCBi001-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01831934	PHASE4	COMPLETED	Responses to Influenza Vaccine in Patients With Mitochondrial Disorders (MELAS)
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT03293524	PHASE3	COMPLETED	Efficacy & Safety Study of Bilateral IVT Injection of GS010 in LHON Subjects Due to the ND4 Mutation for up to 1 Year
NCT03406104	PHASE3	COMPLETED	RESCUE and REVERSE Long-term Follow-up
NCT07406854	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3, Multicenter, Randomized, Double-Masked, Sham-Controlled Clinical Trial for Leber’s Hereditary Optic Neuropathy (LHON) Associated With ND4 Mutation
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT02176733	PHASE2	UNKNOWN	Trial of Cyclosporine in the Acute Phase of Leber Hereditary Optic Neuropathy
NCT00068913	PHASE2	UNKNOWN	Evaluating the Effectiveness of a Dichloroacetate in MELAS Syndrome
NCT00887562	PHASE2	COMPLETED	Study of Idebenone in the Treatment of Mitochondrial Encephalopathy Lactic Acidosis & Stroke-like Episodes
NCT01603446	PHASE2	COMPLETED	L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04475549	PHASE2	TERMINATED	Phase 2a Study of IW-6463 in Adults Diagnosed With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS)
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT06644534	PHASE2	RECRUITING	A Study to Assess TTI-0102 vs Placebo in MELAS Patients
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
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
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
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
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT03056209	PHASE1	COMPLETED	Safety, Tolerability and Pharmacokinetic Study of KL1333 in Healthy Male Volunteers
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT03952234	PHASE1	COMPLETED	L-Citrulline Dose Finding Safety Study in MELAS