MT-ND5

Summary

MT-ND5 (mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 5, HGNC:7461) is a protein-coding gene on chromosome mitochondria, encoding NADH-ubiquinone oxidoreductase chain 5 (P03915). 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 Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome.

Source: NCBI Gene 4540 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +5 more curated relationships
• Clinical variants (ClinVar): 332 total — 4 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 162
• Druggable target: yes

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7461
Approved symbol	MT-ND5
Name	mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 5
Location	mitochondria
Locus type	gene with protein product
Status	Approved
Aliases	ND5, NAD5
Ensembl gene	ENSG00000198786
Ensembl biotype	protein_coding
OMIM	516005
Entrez	4540

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000361567

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

ENST00000361567 — 1 exons

Exon	Start	End
ENSE00001435330	12337	14148

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 100.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2209.2980 / max 815414.8754, expressed in 1827 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194976	2113.9434	1826
194978	42.6479	1770
194979	35.5081	1729
194977	15.0601	1692
194980	2.1384	911

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	100.00	gold quality
postcentral gyrus	UBERON:0002581	100.00	gold quality
lateral nuclear group of thalamus	UBERON:0002736	100.00	gold quality
nasal cavity epithelium	UBERON:0005384	100.00	gold quality
renal medulla	UBERON:0000362	99.99	gold quality
pons	UBERON:0000988	99.99	gold quality
cardia of stomach	UBERON:0001162	99.99	gold quality
parietal lobe	UBERON:0001872	99.99	gold quality
substantia nigra pars compacta	UBERON:0001965	99.99	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.99	gold quality
lateral globus pallidus	UBERON:0002476	99.99	gold quality
ventral tegmental area	UBERON:0002691	99.99	gold quality
entorhinal cortex	UBERON:0002728	99.99	gold quality
jejunal mucosa	UBERON:0000399	99.98	gold quality
medulla oblongata	UBERON:0001896	99.98	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.98	gold quality
subthalamic nucleus	UBERON:0001906	99.98	gold quality
myocardium	UBERON:0002349	99.98	gold quality
superior vestibular nucleus	UBERON:0007227	99.98	gold quality
pylorus	UBERON:0001166	99.97	gold quality
mucosa of stomach	UBERON:0001199	99.97	gold quality
right uterine tube	UBERON:0001302	99.97	gold quality
parotid gland	UBERON:0001831	99.97	gold quality
caudate nucleus	UBERON:0001873	99.97	gold quality
putamen	UBERON:0001874	99.97	gold quality
amygdala	UBERON:0001876	99.97	gold quality
nucleus accumbens	UBERON:0001882	99.97	gold quality
midbrain	UBERON:0001891	99.97	gold quality
substantia nigra	UBERON:0002038	99.97	gold quality
right frontal lobe	UBERON:0002810	99.97	gold quality

Single-cell (SCXA)

Detected in 41 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-MTAB-8060	yes	10634.51
E-CURD-122	yes	10188.48
E-CURD-88	yes	10102.49
E-GEOD-130473	yes	9405.79
E-HCAD-31	yes	9400.14
E-MTAB-9467	yes	5871.40
E-MTAB-10042	yes	5841.49
E-MTAB-6308	yes	5829.90
E-GEOD-137537	yes	5411.53
E-MTAB-8322	yes	5410.35
E-MTAB-10855	yes	4304.46
E-MTAB-10553	yes	3509.31
E-CURD-120	yes	3116.59
E-HCAD-4	yes	114.10
E-MTAB-7316	yes	40.75

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• One proband had a non-synonymous A14062G mutation in the ND5 gene. (PMID:12031626)
• This study conclude that the G13513A mutation causes a complex I defect when present at unusually low mutant load and may act dominantly. (PMID:14520659)
• A 13513G->A transition in ND5 was identified in a 4-year-old Italian boy atypical Leigh syndrome patient (PMID:14557590)
• The expression of MTND5 was studied in blood platelets during aging. There was increased genetic transcription. (PMID:14759509)
• Heteroplasmic mutations largely segregate PD from controls and may be of major pathogenic importance in idiopathic Parkinson disease. (PMID:15596151)
• In cholera, ND5 is upregulated in the mucosa of the small intestine, which correlates with the virulence of Vibrio cholerae. (PMID:15946665)
• we describe the clinical and genetic characterization of a new LHON mtDNA mutation. The 12848T mutation alters a highly conserved amino acid in the ND5 complex I gene. (PMID:16240359)
• Secondary structure analysis of the ND5 protein further supported the deleterious role of the 12706C mutation (PMID:17317336)
• Functional effects of nonsense mitochondrial DNA (mtDNA) mutations in the COXI and ND5 genes in a colorectal tumor cell line. (PMID:17341490)
• Complete screening of the mitochondrial genome of 116 patients detected 4 families with an ND5 mutation (including a new m.13511AT mutation), accounting for 27% of the total number of mtDNA gene mutations. (PMID:17400793)
• MT-ND5 gene variation is significantly associated with brain mitochondrial respiratory function in Tibet chicken embryos under hypoxia. (PMID:17614984)
• In contrast to results reported for PD frontal cortex, low-level ND5 mutations between codons 120 and 150 do not accumulate severely in biochemically affected skeletal muscle samples of Parkinson’s patients. (PMID:17702497)
• ND5 gene is implicated in mitochondrial dysfunction in schizophrenia. (PMID:17898419)
• Mitochondrial ND5 gene variation associated with encephalomyopathy and mitochondrial ATP consumption (PMID:17940288)
• identified the nt13708A variant as a susceptibility allele to multiple sclerosis (PMID:18270557)
• The G13513A mutation is a common cause of MELAS and LS, even in the absence of obvious maternal inheritance, pathological findings in muscle, or severe complex I deficiency. (PMID:18332249)
• We describe a patient with isolated exercise intolerance caused by a new, maternally inherited mutation in heteroplasmic T>C transition at position 13271 in MTND5. (PMID:18396045)
• 13513G>A mutation in the ND5 is associated with Leigh or Leigh-like disease. (PMID:18495510)
• We suggest that mtDNA G13513A mutation is an important factor in patients with Leigh syndrome associated with WPW syndrome and/or optic atrophy. (PMID:19054921)
• article describes 2 mitochondrial DNA mutations in the ND3 and ND5 genes in patients showing clinical features of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (PMID:19617458)
• 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)
• Several lines of evidence suggest that the mitochondrial ND5T12338C mutation is associated with Leber’s hereditary optic neuropathy (LHON) in Chinese families. (PMID:21131053)
• Patients with ND5*13513 G to A mutation may have a characteristic clinical course and ND5 *13513 G to A might be a preferential candidate mutation of Leigh syndrome. (PMID:21154318)
• ND4 G11696A and ND5 T12338C mutation is likely associated with Leber’s hereditary optic neuropathy in two Chinese families (PMID:21482521)
• Mitochondrial DNA mutations in respiratory complex-I in never-smoker lung cancer patients contribute to lung cancer progression in association with EGFR gene mutation. (PMID:21830212)
• Mitochondrial ND5 12338T>C variant is associated with maternally inherited hypertrophic cardiomyopathy in a Chinese pedigree (PMID:22759514)
• Point mutations m.10191T>C in mitochondrial ND3 gene, m.13513G>A in ND5 gene and m.14,453G>A in ND6 gene were detected in three Chinese children with Leigh synrome dur to complex I deficiency. (PMID:22947169)
• Three mutations were significantly related to the presence of epilepsy. These mutations were found at the 8502, 11994, and 13,231 bp of mtDNA, which resulted in amino acid changes at the MT-ATP-8, MT-ND4 and MT-ND5 genes. (PMID:24440288)
• Study demonstrates a link between p53 and Bcl-2 proteins as regulators of ROS production and cellular invasiveness, and reveals complex-I, especially ND5, as their functional target in lung tumor cells. (PMID:25115399)
• Mitochondrially encoded NADH dehydrogenase subunit, complex I extracts energy from NADH, produced by the oxidation of sugars and fats, and traps the energy in a potential difference or voltage across the mitochondrial inner membrane. (PMID:25756807)
• We describe a unique presentation Leber hereditary optic neuropathy (LHON) and mitochondrial encephalopathy, myopathy, lactic acidosis and stroke-like episodes (MELAS) overlap syndrome resulting from a m.13046T>C mutation in a 12-year-old girl. (PMID:26894521)
• The m.13565C>T mutation in MTND5 causes defects in both mitochondrial oxidative metabolism and mitochondrial calcium sequestration in a MELAS syndrome fibroblasts. (PMID:27110715)
• A MELAS/Leigh syndrome phenotype caused by a mtDNA mutation [m.13513G>A; p.Asp393Asn] in the ND5 gene encoding the ND5 subunit of respiratory chain complex I was identified in a patient in a second family (PMID:27344355)
• Data suggest that mutations in MT-CO2 and MT-ND5 can be involved in MIDD (maternally inherited diabetes and deafness); a Tunisian family (mother, daughter, son) with clinical features of MIDD associated with retinopathy exhibit mutations in MT-CO2 (m.8241T>G - p. F219C) and MT-ND5 (m.13276G>A - p. M314V); these two mutations could explain retinopathy in some family members. (MT-CO2 = cytochrome c oxidase subunit II) (PMID:27422531)
• FASTKD4 is required to promote expression of ND5. FASTKD4 may promote processing of ND5-CYB precursor or it may stabilize multiple mature RNAs including ND5. (PMID:28335001)
• MT-ND5 mutation exhibits highly variable neurological manifestations. (PMID:29506874)
• In the present study, we identified a novel mutation of MT-ND5, c.1315A>G (p.Thr439Ala), in a family pedigree using whole-exome sequencing. (PMID:30587702)
• 2 unrelated children with Leigh syndrome were found to have de novo 13513G>A mutations in MTND5. The oculomotor symptoms and blepharoptosis were particularly notable. There was 64% heteroplasmy in the female patient and 72% in the male patient. (PMID:30906981)
• Impact of Mitochondrial Genetic Variants in ND1, ND2, ND5, and ND6 Genes on Sperm Motility and Intracytoplasmic Sperm Injection (ICSI) Outcomes. (PMID:33475980)
• NGS-based mtDNA Profiling Could Reveal Genetic Alterations in Schizophrenia. (PMID:34060999)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mt-nd5	ENSDARG00000063921
mus_musculus	mt-Nd5	ENSMUSG00000064367
rattus_norvegicus	Mt-nd5	ENSRNOG00000029971
drosophila_melanogaster	mt:ND5	FBGN0013684
caenorhabditis_elegans		WBGENE00010967

Paralogs (2): MT-ND2 (ENSG00000198763), MT-ND4 (ENSG00000198886)

Protein

Protein identifiers

NADH-ubiquinone oxidoreductase chain 5 — P03915 (reviewed: P03915)

Alternative names: NADH dehydrogenase subunit 5

All UniProt accessions (2): P03915, U5ZC31

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. Leigh syndrome (LS) [MIM:256000] An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. 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.

Similarity. Belongs to the complex I subunit 5 family.

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001516	Proton_antipo_N	Domain
IPR001750	ND/Mrp_TM	Domain
IPR003945	NU5C-like	Family
IPR010934	NADH_DH_su5_C	Domain
IPR018393	NADHpl_OxRdtase_5_subgr	Family

Pfam: PF00361, PF00662, PF06455

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (41 total): sequence variant 24, transmembrane region 15, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

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

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P03915-F1	92.67	0.82

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: 415 (showing top): GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, 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 (9): response to hypoxia (GO:0001666), mitochondrial electron transport, NADH to ubiquinone (GO:0006120), aerobic respiration (GO:0009060), electron transport coupled proton transport (GO:0015990), mitochondrial respiratory chain complex I assembly (GO:0032981), response to hydrogen peroxide (GO:0042542), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), ATP synthesis coupled electron transport (GO:0042773), proton transmembrane transport (GO:1902600)

GO Molecular Function (1): NADH dehydrogenase (ubiquinone) activity (GO:0008137)

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
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
oxidative phosphorylation	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
energy coupled proton transmembrane transport, against electrochemical gradient	1
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
response to reactive oxygen species	1
mitochondrion	1
proton motive force-driven ATP synthesis	1
respiratory electron transport chain	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
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

2635 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MT-ND5	MT-ND6	P03923	999
MT-ND5	MT-ND4L	P03901	999
MT-ND5	MT-ND3	P03897	999
MT-ND5	MT-ND4	P03905	999
MT-ND5	MT-ND1	P03886	998
MT-ND5	MT-ND2	P03891	993
MT-ND5	MT-CO3	P00414	975
MT-ND5	MT-CYB	P00156	972
MT-ND5	MT-ATP6	P00846	972
MT-ND5	MT-CO1	P00395	967
MT-ND5	MT-ATP8	P03928	959
MT-ND5	MT-CO2	P00403	945
MT-ND5	NDUFS7	O75251	929
MT-ND5	NDUFS8	O00217	902
MT-ND5	NDUFV1	P49821	893

IntAct

96 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
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
ENPP6	SCAMP1	psi-mi:“MI:0914”(association)	0.640
NDUFB5	NDUFB3	psi-mi:“MI:0914”(association)	0.640
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA9	NDUFS4	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFA9	NDUFS8	psi-mi:“MI:0914”(association)	0.530
MRPL50	GTPBP10	psi-mi:“MI:0914”(association)	0.530
NDUFA8	NDUFS8	psi-mi:“MI:0914”(association)	0.530
FUT1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
YIPF3	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
NDUFC2	NDUFS4	psi-mi:“MI:0914”(association)	0.530
NDUFB8	NDUFS4	psi-mi:“MI:0914”(association)	0.530
NDUFA12	NDUFS4	psi-mi:“MI:0914”(association)	0.530
NDUFB5	NDUFS7	psi-mi:“MI:0914”(association)	0.530
MRPL2	GTPBP10	psi-mi:“MI:0914”(association)	0.530

BioGRID (94): ND5 (Affinity Capture-MS), ND5 (Affinity Capture-MS), ND5 (Affinity Capture-MS), ND5 (Affinity Capture-MS), ND5 (Affinity Capture-MS), ND5 (Affinity Capture-MS), ND5 (Affinity Capture-MS), ND5 (Affinity Capture-MS), ND5 (Affinity Capture-MS), ND5 (Affinity Capture-MS), ND5 (Affinity Capture-MS), ND5 (Affinity Capture-MS), ND5 (Affinity Capture-MS), ND5 (Affinity Capture-MS), ND5 (Affinity Capture-MS)

ESM2 similar proteins: O03174, O03205, O21335, O78688, O78756, O79437, O79556, P03915, P03916, P03917, P03918, P03919, P03920, P03921, P03922, P11661, P18940, P24978, P24979, P38602, P41299, P41309, P48176, P48656, P48921, P92485, P92669, P92699, Q00542, Q1HK80, Q2I3G4, Q34879, Q35543, Q35648, Q35813, Q36459, Q38PR2, Q576B4, Q76LN2, Q8W9M6

Diamond homologs: A9RAH0, F1SVK0, O03174, O03205, O21335, O47815, O63908, O78688, O78756, O79411, O79437, P03915, P03916, P03917, P03918, P03919, P03920, P03921, P05510, P10330, P11628, P11661, P15552, P20679, P24978, P24979, P26849, P29388, P29924, P31971, P33607, P34195, P38602, P41299, P41309, P48176, P48656, P48919, P48920, P48921

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MT-ND5	“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 86 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	27	73.3×	8e-44
Respiratory electron transport	27	42.1×	2e-36
Aerobic respiration and respiratory electron transport	25	36.3×	6e-32
Mitochondrial protein degradation	5	9.4×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	23	103.1×	2e-40
proton motive force-driven mitochondrial ATP synthesis	26	85.6×	9e-43
aerobic respiration	26	80.5×	3e-42
mitochondrial respiratory chain complex I assembly	11	56.5×	4e-15

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	8
Uncertain significance	136
Likely benign	71
Benign	96

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
4293139	NC_012920.1(MT-RNR1):m.758T>C	Pathogenic
693516	NC_012920.1(MT-ND5):m.13094T>C	Pathogenic
9689	NC_012920.1(MT-ND6):m.14459G>A	Pathogenic
9702	NC_012920.1(MT-ND5):m.13513G>A	Pathogenic
155889	NC_012920.1(MT-ND5):m.13514A>G	Likely pathogenic
2443068	NC_012920.1(MT-ND5):m.12923G>A	Likely pathogenic
4795905	NC_012920.1(MT-ND5):m.13480G>A	Likely pathogenic
4795906	NC_012920.1(MT-ND5):m.13769_13787del	Likely pathogenic
693440	NC_012920.1(MT-ND5):m.12425del	Likely pathogenic
693512	NC_012920.1(MT-ND5):m.13046T>C	Likely pathogenic
9698	NC_012920.1(MT-ND5):m.12706T>C (p.Phe124Leu)	Likely pathogenic
9703	NC_012920.1(MT-ND5):m.13042G>A	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

3874 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
M:12706:T:C	F124L	0.999
M:12708:C:A	F124L	0.999
M:12708:C:G	F124L	0.999
M:12766:T:C	W144R	0.999
M:12863:G:C	R176P	0.999
M:13030:T:C	W232R	0.999
M:13084:A:C	S250R	0.999
M:13354:T:C	F340L	0.999
M:13356:T:A	F340L	0.999
M:13356:T:G	F340L	0.999
M:13366:G:T	G344W	0.999
M:12643:T:C	F103L	0.998
M:12645:C:A	F103L	0.998
M:12645:C:G	F103L	0.998
M:12768:A:C	W144C	0.998
M:12768:A:T	W144C	0.998
M:12797:T:A	L154H	0.998
M:12797:T:C	L154P	0.998
M:12871:G:C	D179H	0.998
M:13034:T:A	L233H	0.998
M:13034:T:C	L233P	0.998
M:13051:G:C	G239R	0.998
M:13073:T:C	L246P	0.998
M:13076:T:A	L247H	0.998
M:13076:T:C	L247P	0.998
M:13102:G:T	G256W	0.998
M:13233:A:C	K299N	0.998
M:13233:A:T	K299N	0.998
M:13267:G:C	G311R	0.998
M:13406:G:C	R357P	0.998

dbSNP variants (sampled 300 via entrez): RS1057516065 (MT:11896 C>G), RS1057516066 (MT:12010 C>A,T), RS1057516067 (MT:12013 A>G), RS1057516068 (MT:12018 C>G,T), RS1057516069 (MT:14563 C>T), RS1057518882 (MT:14598 T>C), RS1057520074 (MT:10499 A>G), RS1057520099 (MT:12175 T>C), RS1057520103 (MT:14476 G>A,T), RS1057520176 (MT:11428 C>A,T), RS1131692061 (MT:12271 T>C), RS1131692062 (MT:12283 G>A), RS1131692063 (MT:13051 G>A,T), RS118203888 (MT:12258 C>A,T), RS118203889 (MT:12207 G>A)

Disease associations

OMIM: gene MIM:516005 | disease phenotypes: MIM:256000, MIM:540000, MIM:535000, MIM:500009, MIM:618120, MIM:500017, MIM:500001, MIM:545000, MIM:605909

GenCC curated gene-disease

Disease	Classification	Inheritance
Leber hereditary optic neuropathy	Strong	Mitochondrial
maternally-inherited Leigh syndrome	Supportive	Mitochondrial
MELAS syndrome	Supportive	Mitochondrial
MERRF 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 (13): Leigh syndrome (MONDO:0009723), MELAS syndrome (MONDO:0010789), mitochondrial disease (MONDO:0044970), Leber hereditary optic neuropathy (MONDO:0010788), microcephaly (MONDO:0001149), hearing loss disorder (MONDO:0005365), mitochondrial myopathy with reversible cytochrome C oxidase deficiency (MONDO:0010780), mitochondrial complex V (ATP synthase) deficiency, nuclear type 5 (MONDO:0020858), Leigh syndrome, mitochondrial (MONDO:0970944), Leber optic atrophy and dystonia (MONDO:0010772), MERRF syndrome (MONDO:0010790), autosomal recessive early-onset Parkinson disease 6 (MONDO:0011613), maternally-inherited Leigh syndrome (MONDO:0016814)

Orphanet (8): Leigh syndrome (Orphanet:506), MELAS (Orphanet:550), Mitochondrial disease (Orphanet:68380), Leber hereditary optic neuropathy (Orphanet:104), Mitochondrial myopathy with reversible cytochrome C oxidase deficiency (Orphanet:254864), Leber plus disease (Orphanet:99718), MERRF (Orphanet:551), Young-onset Parkinson disease (Orphanet:2828)

HPO phenotypes

162 total (30 of 162 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:0000407	Sensorineural hearing impairment
HP:0000408	Progressive sensorineural hearing impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000519	Developmental cataract
HP:0000529	Progressive visual loss
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:0000622	Blurred vision
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000709	Psychosis
HP:0000716	Depression
HP:0000726	Dementia
HP:0000736	Short attention span
HP:0000739	Anxiety
HP:0000751	Personality changes

GWAS associations

0 associations (top):

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
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
D017243	MERRF Syndrome	C05.651.460.620.530; C10.228.140.163.100.545; C10.228.140.490.375.130.650.700; C10.228.140.490.493.063.650.700; C10.668.491.500.500.550; C16.320.565.189.545; C18.452.132.100.545; C18.452.648.189.545; C18.452.660.560.620.530
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
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
C536024	Marsden syndrome (supp.)
C536035	Maternally Inherited Leigh Syndrome (supp.)
C565276	Parkinson Disease 6, Autosomal Recessive Early-Onset (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2363065 (PROTEIN COMPLEX)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2853826	MT-CO3, MT-ND3, MT-ND4, MT-ND4L, MT-ND5	3	2.00	1	efavirenz;lopinavir;Nucleoside and nucleotide reverse transcriptase inhibitors;ritonavir

ChEMBL bioactivities

8 potent at pChembl≥5 of 18 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 28 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

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

Chemical	Actions (top 5)	PubMed papers
enniatins	affects cotreatment, increases expression, decreases expression	5
beauvericin	affects cotreatment, increases expression, decreases expression	3
Air Pollutants	increases mutagenesis, decreases expression, increases abundance	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Atrazine	decreases expression	2
Cadmium	decreases expression, increases abundance, increases expression	2
Plant Extracts	affects cotreatment, increases expression	2
1-Methyl-4-phenylpyridinium	decreases expression	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
Particulate Matter	decreases expression, increases abundance, increases mutagenesis	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
bisphenol A	decreases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
fucoxanthin	increases expression, decreases reaction	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
ochratoxin A	increases expression, affects cotreatment	1
aflatoxin G1	decreases expression, affects cotreatment	1
aflatoxin B2	affects cotreatment, decreases expression	1
aflatoxin G2	affects cotreatment, decreases expression	1
tris(chloroethyl)phosphate	increases abundance, increases expression	1
diallyl trisulfide	decreases expression	1
nefazodone	decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
licochalcone B	decreases expression	1
BMS-986094	decreases expression	1
mono(carboxy-isooctyl)phthalate	affects expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1

ChEMBL screening assays

4 unique, capped per target: 4 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

3 cell lines: 2 induced pluripotent stem cell, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_AB83	LND554SV.3	Induced pluripotent stem cell	Male
CVCL_C6UM	SBG5	Finite cell line
CVCL_C6UN	SBG5-iPSC	Induced pluripotent stem cell

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
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
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
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