MT-ATP8

Summary

MT-ATP8 (mitochondrially encoded ATP synthase membrane subunit 8, HGNC:7415) is a protein-coding gene on chromosome mitochondria, encoding ATP synthase F(0) complex subunit 8 (P03928). Subunit 8, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain.

Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in proton motive force-driven mitochondrial ATP synthesis. Located in mitochondrion. Part of proton-transporting ATP synthase complex. Implicated in multiple sclerosis and urinary bladder cancer.

Source: NCBI Gene 4509 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial proton-transporting ATP synthase complex deficiency (Supportive, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 88 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 64
• Druggable target: yes

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7415
Approved symbol	MT-ATP8
Name	mitochondrially encoded ATP synthase membrane subunit 8
Location	mitochondria
Locus type	gene with protein product
Status	Approved
Aliases	ATP8, A6L, URFA6L
Ensembl gene	ENSG00000228253
Ensembl biotype	protein_coding
OMIM	516070
Entrez	4509

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000361851

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

ENST00000361851 — 1 exons

Exon	Start	End
ENSE00001435286	8366	8572

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 100.00.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	100.00	gold quality
right ovary	UBERON:0002118	100.00	gold quality
right lung	UBERON:0002167	100.00	gold quality
descending thoracic aorta	UBERON:0002345	100.00	gold quality
metanephros cortex	UBERON:0010533	100.00	gold quality
right hemisphere of cerebellum	UBERON:0014890	100.00	gold quality
pituitary gland	UBERON:0000007	99.99	gold quality
zone of skin	UBERON:0000014	99.99	gold quality
endocervix	UBERON:0000458	99.99	gold quality
vagina	UBERON:0000996	99.99	gold quality
adipose tissue	UBERON:0001013	99.99	gold quality
right lobe of liver	UBERON:0001114	99.99	gold quality
right lobe of thyroid gland	UBERON:0001119	99.99	gold quality
left lobe of thyroid gland	UBERON:0001120	99.99	gold quality
transverse colon	UBERON:0001157	99.99	gold quality
body of stomach	UBERON:0001161	99.99	gold quality
mucosa of stomach	UBERON:0001199	99.99	gold quality
cortex of kidney	UBERON:0001225	99.99	gold quality
right adrenal gland	UBERON:0001233	99.99	gold quality
left adrenal gland	UBERON:0001234	99.99	gold quality
myometrium	UBERON:0001296	99.99	gold quality
left uterine tube	UBERON:0001303	99.99	gold quality
tibial nerve	UBERON:0001323	99.99	gold quality
muscle of leg	UBERON:0001383	99.99	gold quality
skin of abdomen	UBERON:0001416	99.99	gold quality
ascending aorta	UBERON:0001496	99.99	gold quality
skin of leg	UBERON:0001511	99.99	gold quality
thoracic aorta	UBERON:0001515	99.99	gold quality
left coronary artery	UBERON:0001626	99.99	gold quality
minor salivary gland	UBERON:0001830	99.99	gold quality

Single-cell (SCXA)

Detected in 20 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	28681.22
E-CURD-88	yes	17400.53
E-MTAB-11011	yes	15234.84
E-CURD-55	yes	13603.75
E-CURD-120	yes	6547.34
E-MTAB-8498	yes	5219.26
E-HCAD-31	yes	3756.62
E-MTAB-7381	yes	3034.22
E-GEOD-84465	yes	641.22
E-MTAB-9801	yes	333.40
E-MTAB-10287	yes	325.73
E-GEOD-130148	yes	8.73
E-CURD-85	no	9164.79
E-HCAD-15	no	9042.96
E-CURD-7	no	2959.51

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 14)

• Point mutation occurred in mtDNA might be involved in pathogenesis of multiple sclerosis. (PMID:17619138)
• Case Report: absence of mtDNA-encoded ATPase6 and ATPase8 genes in progressive external ophthalmoplegia patient clearly resulted in aberrant synthesis of ATP synthase. (PMID:20082143)
• Patients with irritable bowel syndrome with diarrhea have a higher incidence of MT-ATP 6 and 8 polymorphisms than healthy subjects, implying that the mtDNA polymorphism may play a role in irritable bowel syndrome with diarrhea. (PMID:23840124)
• Mutations in mitochondrial DNA MT-ATP6/8 genes may be responsible for acute episodes of limb weakness. (PMID:24153443)
• 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)
• Mutations in ATP synthase F0 subunit 8 is associated with peripheral neuropathy of diabetes. (PMID:24456990)
• identified 8 changes in ATP6 gene in 36/50 examined breast cancer cell samples and 5 changes in ATP8 gene (10/50); most were homoplasmic changes of missense type; 4 changes (A8439C, G8858C, C9130G and T9119G) had not been described in the literature before (PMID:25110199)
• Mitochondrially encoded ATP synthase, complex V, is an important enzyme that provides energy to be used by the cell through the synthesis of ATP. (PMID:25756807)
• ATP8 genetic polymorphisms associated with breast cancer in Mizoram mongloid population. (PMID:25896597)
• polymorphisms in MT-ATP8 may have an impact on the pathogenesis of BP in the German population. (PMID:25941154)
• Codon optimization is an essential parameter for the efficient allotopic expression of mtDNA genes. (PMID:31981894)
• Homoplasmic deleterious MT-ATP6/8 mutations in adult patients. (PMID:32858252)
• A lack of a definite correlation between male sub-fertility and single nucleotide polymorphisms in sperm mitochondrial genes MT-CO3, MT-ATP6 and MT-ATP8. (PMID:36066780)
• Variants in Human ATP Synthase Mitochondrial Genes: Biochemical Dysfunctions, Associated Diseases, and Therapies. (PMID:38396915)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	mt-Atp8	ENSMUSG00000064356
rattus_norvegicus	Mt-atp8	ENSRNOG00000033299

Protein

Protein identifiers

ATP synthase F(0) complex subunit 8 — P03928 (reviewed: P03928)

Alternative names: A6L, F-ATPase subunit 8

All UniProt accessions (2): P03928, U5YV54

UniProt curated annotations — full annotation on UniProt →

Function. Subunit 8, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. ATP synthase complex consist of a soluble F(1) head domain - the catalytic core - and a membrane F(1) domain - the membrane proton channel. These two domains are linked by a central stalk rotating inside the F(1) region and a stationary peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. In vivo, can only synthesize ATP although its ATP hydrolase activity can be activated artificially in vitro. Part of the complex F(0) domain.

Subunit / interactions. Component of the ATP synthase complex composed at least of ATP5F1A/subunit alpha, ATP5F1B/subunit beta, ATP5MC1/subunit c (homooctamer), MT-ATP6/subunit a, MT-ATP8/subunit 8, ATP5ME/subunit e, ATP5MF/subunit f, ATP5MG/subunit g, ATP5MK/subunit k, ATP5MJ/subunit j, ATP5F1C/subunit gamma, ATP5F1D/subunit delta, ATP5F1E/subunit epsilon, ATP5PF/subunit F6, ATP5PB/subunit b, ATP5PD/subunit d, ATP5PO/subunit OSCP. ATP synthase complex consists of a soluble F(1) head domain (subunits alpha(3) and beta(3)) - the catalytic core - and a membrane F(0) domain - the membrane proton channel (subunits c, a, 8, e, f, g, k and j). These two domains are linked by a central stalk (subunits gamma, delta, and epsilon) rotating inside the F1 region and a stationary peripheral stalk (subunits F6, b, d, and OSCP). Interacts with PRICKLE3.

Subcellular location. Mitochondrion membrane.

Disease relevance. Mitochondrial complex V deficiency, mitochondrial 2 (MC5DM2) [MIM:516070] A mitochondrial disorder with heterogeneous clinical manifestations including neuropathy, ataxia, hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy can present with negligible to extreme hypertrophy, minimal to extensive fibrosis and myocyte disarray, absent to severe left ventricular outflow tract obstruction, and distinct septal contours/morphologies with extremely varying clinical course. The disease is caused by variants affecting the gene represented in this entry. Cardiomyopathy, infantile hypertrophic (CMHI) [MIM:500006] An infantile form of hypertrophic cardiomyopathy, a heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry.

Similarity. Belongs to the ATPase protein 8 family.

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001421	ATP8_metazoa	Family
IPR039017	ATP8_mammal	Family

Pfam: PF00895

UniProt features (15 total): helix 4, sequence variant 4, modified residue 3, sequence conflict 2, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
8H9S	ELECTRON MICROSCOPY	2.53
8H9U	ELECTRON MICROSCOPY	2.61
8H9F	ELECTRON MICROSCOPY	2.69
8H9T	ELECTRON MICROSCOPY	2.77
8KI3	ELECTRON MICROSCOPY	2.89
8H9M	ELECTRON MICROSCOPY	3
8H9V	ELECTRON MICROSCOPY	3.02
8KHF	ELECTRON MICROSCOPY	3.13
8H9J	ELECTRON MICROSCOPY	3.26
8H9Q	ELECTRON MICROSCOPY	3.47

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P03928-F1	73.41	0.21

Functional residue map

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

Post-translational modifications (3): 54, 54, 57

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-163210	Formation of ATP by chemiosmotic coupling
R-HSA-5419276	Mitochondrial translation termination
R-HSA-8949613	Cristae formation
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-1852241	Organelle biogenesis and maintenance

MSigDB gene sets: 213 (showing top): GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, REACTOME_FORMATION_OF_ATP_BY_CHEMIOSMOTIC_COUPLING, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_ATP_BIOSYNTHETIC_PROCESS, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_BIOSYNTHETIC_PROCESS, KEGG_HUNTINGTONS_DISEASE, GOCC_MITOCHONDRIAL_ENVELOPE

GO Biological Process (5): proton motive force-driven ATP synthesis (GO:0015986), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), ATP biosynthetic process (GO:0006754), monoatomic ion transport (GO:0006811), proton transmembrane transport (GO:1902600)

GO Molecular Function (3): proton transmembrane transporter activity (GO:0015078), protein binding (GO:0005515), proton-transporting ATP synthase activity, rotational mechanism (GO:0046933)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), proton-transporting ATP synthase complex (GO:0045259), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Mitochondrial translation	1
Mitochondrial biogenesis	1
Metabolism	1
Organelle biogenesis and maintenance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	2
proton motive force-driven ATP synthesis	2
ATP biosynthetic process	1
oxidative phosphorylation	1
purine ribonucleotide biosynthetic process	1
purine ribonucleoside triphosphate biosynthetic process	1
ATP metabolic process	1
transport	1
monoatomic cation transmembrane transport	1
monoatomic cation transmembrane transporter activity	1
proton transmembrane transport	1
binding	1
proton channel activity	1
ligase activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
proton-transporting two-sector ATPase complex	1
cation channel complex	1
respiratory chain complex	1
catalytic complex	1
cellular anatomical structure	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

800 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MT-ATP8	MT-ATP6	P00846	999
MT-ATP8	MT-ND4L	P03901	974
MT-ATP8	MT-ND5	P03915	959
MT-ATP8	MT-ND4	P03905	958
MT-ATP8	MT-ND3	P03897	958
MT-ATP8	MT-CO3	P00414	946
MT-ATP8	MT-CYB	P00156	923
MT-ATP8	MT-ND6	P03923	923
MT-ATP8	MT-ND2	P03891	921
MT-ATP8	MT-CO2	P00403	913
MT-ATP8	MT-ND1	P03886	889
MT-ATP8	PTGS1	P23219	882
MT-ATP8	MT-CO1	P00395	881
MT-ATP8	ATPAF2	Q8N5M1	878
MT-ATP8	TMEM70	Q9BUB7	875

IntAct

59 interactions, top by confidence:

A	B	Type	Score
ATP5PF	ATP5PD	psi-mi:“MI:0914”(association)	0.670
ATP5PB	SLC19A2	psi-mi:“MI:0914”(association)	0.640
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
HTR2C	KLRG2	psi-mi:“MI:0914”(association)	0.530
DKK3	NME4	psi-mi:“MI:0914”(association)	0.530
ATP5F1D	NDUFB5	psi-mi:“MI:0914”(association)	0.530
ATP5ME	SLC19A2	psi-mi:“MI:0914”(association)	0.530
ATP5PF	SLC19A2	psi-mi:“MI:0914”(association)	0.530
ATP5F1B	SCAMP2	psi-mi:“MI:0914”(association)	0.530
SLC33A1	METTL8	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
P2RY6	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC15A3		psi-mi:“MI:0914”(association)	0.350
UNC93B1		psi-mi:“MI:0914”(association)	0.350
P2RY6		psi-mi:“MI:0914”(association)	0.350
SLC27A3	RCCD1	psi-mi:“MI:0914”(association)	0.350
ATP5F1D		psi-mi:“MI:0914”(association)	0.350
FPR2	GPR89A	psi-mi:“MI:0914”(association)	0.350
TACR1	GPR89A	psi-mi:“MI:0914”(association)	0.350
VIPR1	GPR89A	psi-mi:“MI:0914”(association)	0.350
ZFYVE27	PSMD11	psi-mi:“MI:0914”(association)	0.350
ATP5F1B	ATP5PD	psi-mi:“MI:0914”(association)	0.350
	ATP6AP2	psi-mi:“MI:0914”(association)	0.350
AVPR2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
TSPAN31	TMEM120B	psi-mi:“MI:0914”(association)	0.350
OPRL1	METTL15	psi-mi:“MI:0914”(association)	0.350

BioGRID (57): ATP8 (Affinity Capture-MS), ATP8 (Affinity Capture-MS), ATP8 (Affinity Capture-MS), ATP8 (Affinity Capture-MS), ATP8 (Affinity Capture-MS), ATP8 (Affinity Capture-MS), ATP8 (Affinity Capture-MS), ATP8 (Affinity Capture-MS), ATP8 (Affinity Capture-MS), ATP8 (Affinity Capture-MS), ATP8 (Affinity Capture-MS), ATP8 (Affinity Capture-MS), ATP8 (Affinity Capture-MS), ATP8 (Affinity Capture-MS), ATP8 (Affinity Capture-MS)

ESM2 similar proteins: O03168, O21329, O21401, O47871, O63913, O79396, O79405, O79431, O79550, O79674, P03928, P03931, P14093, P14414, P15996, P24947, P34190, P50655, P50682, P68528, P68529, P92663, Q34571, Q34801, Q35416, Q35537, Q35587, Q35647, Q36362, Q36453, Q4JQI3, Q8HFZ6, Q8HG02, Q95912, Q9MDJ1, Q9ME31, Q9MIY6, Q9TA07, Q9TBI5, Q9TBI6

Diamond homologs: O03199, O21329, O63902, O78751, O79431, O99598, P03928, P03929, P03930, P11608, P14414, P24947, P24949, P38592, P41292, P41314, P48663, P48896, P92479, P92663, P92694, Q00522, Q32643, Q34571, Q34801, Q35584, Q35587, Q35647, Q35914, Q36453, Q3L6W9, Q3L6Z3, Q5Y4Q6, Q6EMS7, Q8HFZ6, Q8HG02, Q8LX28, Q8W9N2, Q94NW9, Q95705

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MT-ATP8	“form complex”	“ATP synthase”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 72 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
Formation of ATP by chemiosmotic coupling	7	86.9×	2e-10
Cristae formation	7	52.7×	6e-09
Mitochondrial biogenesis	7	25.6×	8e-07
Aerobic respiration and respiratory electron transport	8	15.4×	3e-06
Mitochondrial protein degradation	6	14.9×	2e-04
Organelle biogenesis and maintenance	7	10.1×	3e-04
G alpha (q) signalling events	7	8.7×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
proton motive force-driven ATP synthesis	7	86.4×	5e-10
proton motive force-driven mitochondrial ATP synthesis	8	32.4×	3e-08
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	5	16.8×	1e-03
phospholipase C-activating G protein-coupled receptor signaling pathway	7	14.2×	9e-05
G protein-coupled receptor signaling pathway	9	5.0×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	31
Likely benign	17
Benign	32

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
430676	NC_012920.1(MT-TS2):m.7129_13991del	Pathogenic
590888	NC_012920.1(MT-ATP8):m.8431_8432insCCA	Pathogenic
626321	NC_012920.1(MT-ATP8):m.8420_8421insATA	Pathogenic
4795904	NC_012920.1(MT-ATP8):m.8472dup	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

425 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
M:8553:C:G	F9L	0.979
M:8544:C:G	F6L	0.970
M:8543:T:G	F6C	0.959
M:8552:T:G	F9C	0.927
M:8552:T:C	F9S	0.896
M:8542:T:A	F6I	0.894
M:8542:T:G	F6V	0.870
M:8390:T:C	W9R	0.857
M:8543:T:C	F6S	0.845
M:8528:T:C	W55R	0.792
M:8551:T:A	F9I	0.783
M:8561:C:G	P12R	0.771
M:8561:C:A	P12H	0.769
M:8392:G:C	W9C	0.759
M:8392:G:T	W9C	0.759
M:8426:T:C	F21L	0.745
M:8428:C:A	F21L	0.745
M:8428:C:G	F21L	0.745
M:8549:C:G	S8W	0.737
M:8561:C:T	P12L	0.737
M:8551:T:G	F9V	0.735
M:8540:T:A	L5Q	0.727
M:8543:T:A	F6Y	0.725
M:8540:T:G	L5R	0.698
M:8518:A:C	W51C	0.685
M:8518:A:T	W51C	0.685
M:8538:T:A	N4K	0.663
M:8538:T:G	N4K	0.663
M:8421:C:A	T19K	0.662
M:8516:T:C	W51R	0.658

dbSNP variants (sampled 300 via entrez): RS1029294 (MT:6473 C>T), RS1041840 (MT:6383 G>A), RS1057516060 (MT:7373 A>G), RS1057516061 (MT:7496 T>C), RS1057516062 (MT:8418 T>C), RS1057518824 (MT:8084 A>G,T), RS1057520102 (MT:8816 A>G), RS1057520115 (MT:8260 T>C), RS1057520204 (MT:8943 C>T), RS1064597 (MT:8647 C>G), RS111033173 (MT:7468 C>A,T), RS111033319 (MT:7465 AC>A,ACC), RS111033324 (MT:7498 G>A), RS1116904 (MT:8027 G>A,T), RS1116905 (MT:8428 C>A,T)

Disease associations

OMIM: gene MIM:516070 | disease phenotypes: MIM:256000

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial proton-transporting ATP synthase complex deficiency	Supportive	Autosomal recessive
periodic paralysis with later-onset distal motor neuropathy	Supportive	Mitochondrial
mitochondrial disease	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Limited	MT

Mondo (5): Leigh syndrome (MONDO:0009723), optic nerve disorder (MONDO:0002135), mitochondrial disease (MONDO:0044970), mitochondrial proton-transporting ATP synthase complex deficiency (MONDO:0014471), periodic paralysis with later-onset distal motor neuropathy (MONDO:0018343)

Orphanet (2): Leigh syndrome (Orphanet:506), Mitochondrial disease (Orphanet:68380)

HPO phenotypes

64 total (30 of 64 shown, HPO-id order):

HPO	Term
HP:0000089	Renal hypoplasia
HP:0000135	Hypogonadism
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000467	Neck muscle weakness
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000510	Rod-cone dystrophy
HP:0000518	Cataract
HP:0000580	Pigmentary retinopathy
HP:0000590	Progressive external ophthalmoplegia
HP:0000602	Ophthalmoplegia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000726	Dementia
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0000823	Delayed puberty
HP:0000829	Hypoparathyroidism
HP:0000830	Anterior hypopituitarism
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy

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
D009901	Optic Nerve Diseases	C10.292.700; C11.640

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066980 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — F-type ATPase

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
enniatins	affects cotreatment, affects expression, decreases expression	5
Air Pollutants	decreases expression, increases abundance, increases mutagenesis	5
beauvericin	affects cotreatment, affects expression, decreases expression	3
Particulate Matter	decreases expression, increases abundance, increases mutagenesis	3
bisphenol A	decreases expression, decreases reaction, increases abundance	2
Atrazine	decreases expression	2
Plant Extracts	affects cotreatment, increases expression, decreases expression	2
Valproic Acid	affects response to substance, decreases expression	2
ginger extract	decreases expression, decreases reaction, increases abundance	1
methylmercuric chloride	increases expression	1
lead acetate	decreases expression	1
di-n-octyl phthalate	decreases expression	1
methylparaben	decreases expression	1
tetrabromobisphenol A	increases expression	1
ochratoxin A	decreases expression, increases expression, affects cotreatment	1
aflatoxin G1	affects cotreatment, decreases expression, increases expression	1
ferrous chloride	decreases expression	1
aflatoxin B2	increases expression, affects cotreatment, decreases expression	1
aflatoxin G2	affects cotreatment, decreases expression, increases expression	1
2-chloroethyl ethyl sulfide	decreases expression	1
dimethoxyethyl phthalate	decreases expression	1
1-methyl-4-phenyl-2,3-dihydropyridinium	decreases expression	1
nefazodone	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
licochalcone B	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
alpha-Chlorohydrin	decreases expression	1
Cadmium	increases abundance, increases expression	1
Diethylhexyl Phthalate	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652934	Binding	Binding affinity to human MT-ATP8 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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
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)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
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
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)
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)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
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
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy