MT-ATP6

Summary

MT-ATP6 (mitochondrially encoded ATP synthase membrane subunit 6, HGNC:7414) is a protein-coding gene on chromosome mitochondria, encoding ATP synthase F(0) complex subunit a (P00846). Subunit a, 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.

Enables proton channel activity. Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in proton motive force-driven mitochondrial ATP synthesis and proton transmembrane transport. Located in mitochondrion. Part of proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson’s disease; multiple sclerosis; and systemic lupus erythematosus.

Source: NCBI Gene 4508 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +8 more curated relationships
• Clinical variants (ClinVar): 308 total — 8 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 160
• Druggable target: yes

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7414
Approved symbol	MT-ATP6
Name	mitochondrially encoded ATP synthase membrane subunit 6
Location	mitochondria
Locus type	gene with protein product
Status	Approved
Aliases	ATP6, ATPase-6, Su6m
Ensembl gene	ENSG00000198899
Ensembl biotype	protein_coding
OMIM	516060
Entrez	4508

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000361899

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

ENST00000361899 — 1 exons

Exon	Start	End
ENSE00001727012	8527	9207

Expression profiles

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

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.4634 / max 3530.9891, expressed in 1456 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194895	10.3542	1394
194896	1.1092	379

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	100.00	gold quality
left uterine tube	UBERON:0001303	100.00	gold quality
descending thoracic aorta	UBERON:0002345	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
adult mammalian kidney	UBERON:0000082	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
rectum	UBERON:0001052	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
vermiform appendix	UBERON:0001154	99.99	gold quality
transverse colon	UBERON:0001157	99.99	gold quality
body of stomach	UBERON:0001161	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
right uterine tube	UBERON:0001302	99.99	gold quality
tibial nerve	UBERON:0001323	99.99	gold quality
gastrocnemius	UBERON:0001388	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
right coronary artery	UBERON:0001625	99.99	gold quality
left coronary artery	UBERON:0001626	99.99	gold quality

Single-cell (SCXA)

Detected in 74 experiment(s), a significant marker in 34.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	59268.10
E-MTAB-10855	yes	43987.70
E-CURD-77	yes	27051.92
E-CURD-122	yes	24148.99
E-MTAB-6505	yes	21441.05
E-GEOD-180759	yes	20492.97
E-CURD-55	yes	20258.64
E-MTAB-8271	yes	18060.80
E-CURD-79	yes	17524.25
E-MTAB-6701	yes	17033.83
E-HCAD-5	yes	16848.53
E-HCAD-1	yes	16678.89
E-MTAB-10885	yes	16260.48
E-MTAB-10553	yes	16063.32
E-MTAB-7407	yes	15061.09

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BSX, ESR1, ESR2, FOXC2, MYB, MYC, TBP, TBPL1, TTF1, USF2, YY1, ZBED1

Literature-anchored findings (GeneRIF, showing 40)

• Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus (PMID:11925565)
• ATP6L is upregulated in resonse to antineoplastic agents as an anti-apoptotic defense (PMID:12133827)
• A mitochondrial DNA microdeletion removes the termination codon for MTATP6 and sets MTCO3 immediately in frame. (PMID:12915481)
• mitochondrial ATP6 can use GUG as a functional initiation codon (PMID:14697245)
• This work provides the first evidence that hyperpolarization of mitochondria may be a ‘risk factor’ for cells with a deep ATPase dysfunction, such as cells from patients with maternally-inherited Leigh syndrome (PMID:15228605)
• 25 amino acids are probably the human-specific adaptation residues of ATP6 (PMID:15965056)
• The spectrum of mutations causing Leigh syndrome and emphasize the role of MTATP6 gene mutations in pathogenesis of Leigh syndrome. (PMID:16217706)
• The data also demonstrate that mutations in either of these genes may cause early deafness, and they highlight the importance of genetic screening for recessive forms of dRTA independent of hearing status. (PMID:16611712)
• Hybrid ATP6 mRNAs, as the endogenous SOD2 mRNA, localize to the mitochondrial surface in human cells. (PMID:16751614)
• ATP synthase dimers and higher homo-oligomers were observed for the first time, and it was demonstrated that the mutant enzymes retain enough structural integrity to oligomerize (PMID:17121862)
• Reliability of preimplantation genetic diagnosis for T8993G mutation. (PMID:17342424)
• These results possibly highlight the different pathogenic mechanism generated by the two mutations at position 8993 of ATPase 6 subunit of the mitochondrial ATP synthase complex. (PMID:17568559)
• Point mutation occurred in mtDNA might be involved in pathogenesis of multiple sclerosis. (PMID:17619138)
• In a 3-generation ataxic family with the m.8993T–>C mutation of mtDNA, 1 had episodic ataxia & transient hemipareses, broadening the phenotype. No further cases were identified in an additional cohort of 191 patients with suspected EA. (PMID:18055910)
• mitochondrial 12S/MT-RNR1, MT-CO2/COX2, and MT-ATP6 transcripts is significantly decreased in prostate tumor samples (PMID:18409190)
• This paper emphasises the role of MTATP6 in LS and expands the associated clinical phenotype further. (PMID:18461509)
• fibroblast phenotype study of the four most frequent mutations in the ATPase6 gene, namely L156R, L217R, L156P, and L217P (PMID:19160410)
• Results indicate that a mutation in mitochondrial ATPase 6 does not affect the proton permeability of the mitochondrial inner membrane. (PMID:19269308)
• To gain insight into the primary pathogenic mechanisms induced by mtDNA Atp6p T9176C, we have investigated the consequences of this mutation on the ATP synthase of yeast where Atp6p is also encoded by the mtDNA. (PMID:20056103)
• 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)
• ATPase6 gene nucleotide alterations and elevated Reactive Oxygen Species levels occur in idiopathic cases of Primary ovarian insufficiency (POI) (PMID:20361200)
• The authors report a rare mutation, m. 9185 T>C that gives rise to a progressive, but episodic pattern of neurological impairment with partial recovery in Leigh syndrome. (PMID:20546952)
• Mitochondrial ATP6 point mutation associated with hereditary spastic paraplegia-like disorder. (PMID:20656066)
• differences in the biosynthesis and remodeling of cardiolipin at the level of the inner mitochondrial transmembrane related to some mutations of the ATP6 gene. (PMID:21993659)
• Several genes expressed at exceptionally high levels were identified associated with early oocyte development, TMEFF2, the Rho-GTPase-activating protein oligophrenin 1 (OPHN1) and the mitochondrial-encoded ATPase6 (ATP6). (PMID:22238370)
• genetic study of Leigh syndrome which showed a novel mutation at 8597T>C of the mitochondrial ATPase6 gene. (PMID:22348497)
• data demonstrated that mtDNA mutations within the ATPase6 gene are a frequent event in Chinese patients with osteosarcoma (PMID:22542792)
• study describes two families with adult-onset spinocerebellar ataxia due to mutations in MTATP6. (PMID:22577227)
• A family members with m.8993T>C mutation in the mitochondrial MT-ATP6 gene have neuropathy ataxia and retinis pigmentosa/maternally inherited Leigh syndrome. (PMID:22819295)
• We have shown that m.9185T>C in MT-ATP6 causes Charcot-Marie-Tooth disease type 2 in 1.1% of genetically undefined cases. (PMID:22933740)
• Our findings reveal that an axonal Charcot Marie Tooth phenotype can be associated with mutations in the mitochondrial ATP6 gene (PMID:22971232)
• study reports the second known family with a rare, maternally inherited missense m.8851T>C mutation in the mitochondrial MTATP6 gene; novel laboratory and muscle biopsy findings in the patient and a new clinical presentation in her mother were observed (PMID:23206802)
• 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)
• This study suggests that, in part, polymorphisms in the MT-ATP6 and MT-CYB genes may contribute to the unexpected fertilization failure. (PMID:24102627)
• Mutations in mitochondrial DNA MT-ATP6/8 genes may be responsible for acute episodes of limb weakness. (PMID:24153443)
• Screening of the MT-ATP6 gene in a large collection of patients suspected of suffering different mitochondrial DNA (mtDNA) disorders. Biochemical, molecular-genetics and other analyses show three new pathologic mutations. (PMID:24986921)
• Here, we report on a neonate with the m.8993 T>G mutation and emphasize implications of mtDNA disorders on family planning decisions. (PMID:25009317)
• 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)
• Two synonymous substitutions (mt.8614T>C and mt.8994G>A) in the mt-ATP6 gene may be associated with childhood obesity; study provides first data about mitochondrial genome variations in a Turkish obese population and also the first in obese children (PMID:25541891)
• Five mutations able to change amino acid synthesis for the ATP synthase subunit 6 were associated with acute lymphoblastic leukemia in a Saudi Arabian cohort. (PMID:25556488)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mt-atp6	ENSDARG00000063911
mus_musculus	mt-Atp6	ENSMUSG00000064357
rattus_norvegicus	Mt-atp6	ENSRNOG00000031979
drosophila_melanogaster	mt:ATPase6	FBGN0013672

Protein

Protein identifiers

ATP synthase F(0) complex subunit a — P00846 (reviewed: P00846)

Alternative names: F-ATPase protein 6, Proton-conducting channel, ATP synthase F(0) complex subunit a

All UniProt accessions (2): P00846, Q0ZFE3

UniProt curated annotations — full annotation on UniProt →

Function. Subunit a, 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. With the subunit c (ATP5MC1), forms the proton-conducting channel in the F(0) domain, that contains two crucial half-channels (inlet and outlet) that facilitate proton movement from the mitochondrial intermembrane space (IMS) into the matrix. Protons are taken up via the inlet half-channel and released through the outlet half-channel, following a Grotthuss mechanism.

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 DNAJC30; interaction is direct.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Neuropathy, ataxia, and retinitis pigmentosa (NARP) [MIM:551500] A syndrome characterized by variable combination of developmental delay, psychomotor retardation, hearing loss, optic atrophy and retinitis pigmentosa, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy. The disease is caused by variants affecting the gene represented in this entry. 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 infantile bilateral striatal necrosis (MIBSN) [MIM:500003] Bilateral striatal necrosis is a neurological disorder resembling Leigh syndrome. The disease is caused by variants affecting the gene represented in this entry. Mitochondrial complex V deficiency, mitochondrial 1 (MC5DM1) [MIM:500015] 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. Myopathy, lactic acidosis, and sideroblastic anemia 3 (MLASA3) [MIM:500011] A rare mitochondrial disorder characterized by sideroblastic anemia, muscle weakness, and exercise intolerance associated with persistent lactic acidemia. Additional MLASA3 features are failure to thrive, hearing loss, epilepsy, stroke-like episodes, and severe developmental delay. The disease is caused by variants affecting the gene represented in this entry. Ataxia and polyneuropathy, adult-onset (APAO) [MIM:500010] A mitochondrial disease characterized by ataxia, axonal sensorimotor polyneuropathy, abnormal eye movements, and dysarthria. 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 the gene represented in this entry.

Similarity. Belongs to the ATPase A chain family.

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000568	ATP_synth_F0_asu	Family
IPR023011	ATP_synth_F0_asu_AS	Active_site
IPR035908	F0_ATP_A_sf	Homologous_superfamily
IPR045083	ATP_synth_F0_asu_bact/mt	Family

Pfam: PF00119

Catalyzed reactions (Rhea), 1 shown:

• H(+)(in) = H(+)(out) (RHEA:34979)

UniProt features (52 total): sequence variant 31, helix 12, transmembrane region 6, chain 1, strand 1, turn 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-P00846-F1	88.92	0.54

Function

Pathways and Gene Ontology

Reactome pathways

9 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-9837999	Mitochondrial protein degradation
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
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 378 (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_RESPONSE_TO_INCREASED_OXYGEN_LEVELS, 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 (6): proton motive force-driven ATP synthesis (GO:0015986), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), response to hyperoxia (GO:0055093), proton transmembrane transport (GO:1902600), ATP biosynthetic process (GO:0006754), monoatomic ion transport (GO:0006811)

GO Molecular Function (4): proton channel activity (GO:0015252), protein binding (GO:0005515), proton transmembrane transporter activity (GO:0015078), proton-transporting ATP synthase activity, rotational mechanism (GO:0046933)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), proton-transporting ATP synthase complex (GO:0045259), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
proton motive force-driven ATP synthesis	2
ATP biosynthetic process	1
mitochondrion	1
oxidative phosphorylation	1
response to stress	1
response to increased oxygen levels	1
monoatomic cation transmembrane transport	1
purine ribonucleotide biosynthetic process	1
purine ribonucleoside triphosphate biosynthetic process	1
ATP metabolic process	1
transport	1
monoatomic cation channel activity	1
proton transmembrane transporter activity	1
binding	1
monoatomic cation transmembrane transporter activity	1
proton transmembrane transport	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

Protein interactions and networks

STRING

2784 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MT-ATP6	MT-ATP8	P03928	999
MT-ATP6	MT-CO3	P00414	978
MT-ATP6	MT-ND3	P03897	974
MT-ATP6	MT-ND4L	P03901	974
MT-ATP6	MT-ND6	P03923	974
MT-ATP6	MT-CYB	P00156	973
MT-ATP6	MT-ND5	P03915	972
MT-ATP6	MT-ND2	P03891	968
MT-ATP6	MT-ND4	P03905	962
MT-ATP6	MT-ND1	P03886	956
MT-ATP6	MT-CO1	P00395	947
MT-ATP6	MT-CO2	P00403	920
MT-ATP6	PTGS1	P23219	884
MT-ATP6	ATPAF2	Q8N5M1	845
MT-ATP6	UQCRFS1	P47985	791

IntAct

44 interactions, top by confidence:

A	B	Type	Score
ATP5PF	SLC19A2	psi-mi:“MI:0914”(association)	0.530
DNAJC30	MT-ATP6	psi-mi:“MI:0915”(physical association)	0.520
	CYB5B	psi-mi:“MI:0914”(association)	0.500
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
SP1	MT-ATP6	psi-mi:“MI:0915”(physical association)	0.370
APP	MT-ATP6	psi-mi:“MI:0915”(physical association)	0.370
Ubr5	SFI1	psi-mi:“MI:0914”(association)	0.350
Ncstn	DERL1	psi-mi:“MI:0914”(association)	0.350
Ten1	IQGAP3	psi-mi:“MI:0914”(association)	0.350
Wdr5	MGA	psi-mi:“MI:0914”(association)	0.350
REEP5	CNOT1	psi-mi:“MI:0914”(association)	0.350
SLC33A1	METTL8	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
APP	MGST3	psi-mi:“MI:0914”(association)	0.350
rep	GPR89A	psi-mi:“MI:0914”(association)	0.350
MT-ATP6	ATP5MC2	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
ATP5PF	TMEM120B	psi-mi:“MI:0914”(association)	0.350
ATP5F1C	EI24	psi-mi:“MI:0914”(association)	0.350

BioGRID (41): ATP6 (Two-hybrid), ATP6 (Two-hybrid), ATP6 (PCA), ATP6 (Affinity Capture-MS), ATP6 (Affinity Capture-MS), ATP6 (Affinity Capture-MS), ATP6 (Affinity Capture-MS), ATP6 (Affinity Capture-MS), ATP6 (Affinity Capture-MS), ATP6 (Affinity Capture-MS), ATP6 (Proximity Label-MS), ATP6 (Proximity Label-MS), ATP6 (Proximity Label-MS), ATP6 (Affinity Capture-MS), ATP6 (Affinity Capture-MS)

ESM2 similar proteins: O03200, O03570, O21330, O21402, O78752, O79432, P00846, P00847, P00848, P05504, P14092, P14413, P24945, P38591, P41291, P41313, P48662, P48894, P50654, P50681, P92480, P92664, P92695, Q00521, Q1HKB1, Q2I3G9, Q32644, Q35915, Q35920, Q36454, Q36964, Q38PR7, Q7YCA5, Q8LTZ5, Q8LX27, Q8W9G8, Q8W9N1, Q94UY0, Q95706, Q95913

Diamond homologs: A9RAH2, O03169, O03200, O03359, O03570, O21004, O21330, O21402, O47426, O47494, O47872, O63912, O78684, O78752, O79406, O79432, O79551, O79675, O99821, P00846, P00847, P00848, P00849, P00850, P00851, P05504, P12696, P14092, P14413, P14569, P15995, P21535, P24945, P24946, P25005, P26853, P33507, P34191, P34834, P38591

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 53 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	5	92.1×	5e-07
Cristae formation	5	55.8×	4e-06
Mitochondrial biogenesis	5	27.1×	9e-05
Mitochondrial protein degradation	5	18.4×	4e-04
Aerobic respiration and respiratory electron transport	6	17.1×	9e-05
Organelle biogenesis and maintenance	6	12.8×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
proton motive force-driven ATP synthesis	5	105.6×	3e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	9
Uncertain significance	115
Likely benign	66
Benign	86

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
590899	NC_012920.1(MT-ATP6):m.8752_8753insAAA	Pathogenic
590998	NC_012920.1(MT-ATP8):m.8562_8564dup	Pathogenic
638146	NC_012920.1(MT-TS2):m.8480_13440del	Pathogenic
638147	NC_012920.1(MT-TS2):m.8350_13450del	Pathogenic
9641	NC_012920.1(MT-ATP6):m.8993T>G	Pathogenic
9642	NC_012920.1(MT-ATP6):m.8993T>C	Pathogenic
9644	NC_012920.1(MT-ATP6):m.9176T>C	Pathogenic
9647	NC_012920.1(MT-ATP6):m.9185T>C	Pathogenic
191364	NC_012920.1(MT-ATP6):m.8969G>A	Likely pathogenic
40153	NC_012920.1(MT-ATP6):m.9191T>C	Likely pathogenic
690280	NC_012920.1(MT-ATP6):m.9035T>C	Likely pathogenic
693047	NC_012920.1(MT-ATP6):m.8993_8994inv	Likely pathogenic
9640	NC_012920.1(MT-ATP8):m.8528T>C	Likely pathogenic
9646	NC_012920.1(MT-CO3):m.9205_9206del	Likely pathogenic
9648	NC_012920.1(MT-ATP6):m.8618dup	Likely pathogenic
9650	NC_012920.1(MT-ATP6):m.9176T>G	Likely pathogenic
986472	NC_012920.1(MT-ATP6):m.9155A>G	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1437 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
M:9032:T:C	L169P	0.992
M:9166:T:C	F214L	0.992
M:9168:C:A	F214L	0.992
M:9168:C:G	F214L	0.992
M:8960:A:T	E145V	0.990
M:9015:C:A	N163K	0.990
M:9015:C:G	N163K	0.990
M:9134:A:T	E203V	0.988
M:8800:T:C	F92L	0.987
M:8802:T:A	F92L	0.987
M:8802:T:G	F92L	0.987
M:8851:T:C	W109R	0.987
M:9156:A:C	Q210H	0.987
M:9156:A:T	Q210H	0.987
M:9011:C:A	A162D	0.986
M:9135:A:C	E203D	0.984
M:9135:A:T	E203D	0.984
M:9005:T:C	L160P	0.982
M:8775:C:A	N83K	0.981
M:8775:C:G	N83K	0.981
M:8961:A:C	E145D	0.981
M:8961:A:T	E145D	0.981
M:9035:T:A	L170H	0.981
M:9044:T:C	L173P	0.981
M:9010:G:C	A162P	0.980
M:9026:G:A	G167D	0.980
M:8551:T:C	F9L	0.979
M:8553:C:A	F9L	0.979
M:8553:C:G	F9L	0.979
M:8728:T:C	W68R	0.979

dbSNP variants (sampled 300 via entrez): RS1057516060 (MT:7373 A>G), RS1057516061 (MT:7496 T>C), RS1057516062 (MT:8418 T>C), RS1057516063 (MT:9166 T>C), RS1057516064 (MT:9237 G>A), RS1057518824 (MT:8084 A>G,T), RS1057520079 (MT:9091 A>G), 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)

Disease associations

OMIM: gene MIM:516060 | disease phenotypes: MIM:256000, MIM:500011, MIM:535000, MIM:540000, MIM:500017, MIM:551500, MIM:557000, MIM:500009, MIM:500000, MIM:500006, MIM:500015, MIM:500010, MIM:500003, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
NARP syndrome	Definitive	Mitochondrial
Leber hereditary optic neuropathy	Supportive	Mitochondrial
familial infantile bilateral striatal necrosis	Supportive	Autosomal dominant
mitochondrial proton-transporting ATP synthase complex deficiency	Supportive	Autosomal recessive
maternally-inherited Leigh syndrome	Supportive	Mitochondrial
maternally-inherited spastic paraplegia	Supportive	Mitochondrial
periodic paralysis with later-onset distal motor neuropathy	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 (27): mitochondrial disease (MONDO:0044970), Leigh syndrome (MONDO:0009723), myopathy, lactic acidosis, and sideroblastic anemia 3 (MONDO:0010782), Leber hereditary optic neuropathy (MONDO:0010788), MELAS syndrome (MONDO:0010789), optic nerve disorder (MONDO:0002135), hereditary ataxia (MONDO:0100309), Leigh syndrome, mitochondrial (MONDO:0970944), NARP syndrome (MONDO:0010794), Pearson syndrome (MONDO:0010797), mitochondrial myopathy with reversible cytochrome C oxidase deficiency (MONDO:0010780), cerebellar ataxia (MONDO:0000437), gonadal dysgenesis (MONDO:0001967), peripheral neuropathy (MONDO:0005244), histiocytoid cardiomyopathy (MONDO:0010771)

Orphanet (15): Mitochondrial disease (Orphanet:68380), Leigh syndrome (Orphanet:506), Leber hereditary optic neuropathy (Orphanet:104), Mitochondrial myopathy and sideroblastic anemia (Orphanet:2598), MELAS (Orphanet:550), Hereditary ataxia (Orphanet:183518), NARP syndrome (Orphanet:644), Pearson syndrome (Orphanet:699), Mitochondrial myopathy with reversible cytochrome C oxidase deficiency (Orphanet:254864), Rare ataxia (Orphanet:102002), Histiocytoid cardiomyopathy (Orphanet:137675), MT-ATP6-related mitochondrial spastic paraplegia (Orphanet:320360), Charcot-Marie-Tooth disease type 1A (Orphanet:101081), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), OBSOLETE: Postaxial polydactyly of fingers (Orphanet:294942)

HPO phenotypes

160 total (30 of 160 shown, HPO-id order):

HPO	Term
HP:0000089	Renal hypoplasia
HP:0000091	Abnormal renal tubule morphology
HP:0000135	Hypogonadism
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000488	Retinopathy
HP:0000508	Ptosis
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000518	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: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:0000726	Dementia
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0000763	Sensory neuropathy

GWAS associations

0 associations (top):

MeSH disease descriptors (13)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D006059	Gonadal Dysgenesis	C12.050.351.875.253.309; C12.200.706.316.309; C12.800.316.309; C16.131.939.316.309; C19.391.119.309
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
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
C564020	Ataxia and Polyneuropathy, Adult-Onset (supp.)
C535584	Cardiomyopathy, infantile histiocytoid (supp.)
C531684	Hereditary spinal ataxia (supp.)
C536035	Maternally Inherited Leigh Syndrome (supp.)
C537396	Neuropathy ataxia and retinitis pigmentosa (supp.)
C564025	Striatonigral Degeneration, Infantile, Mitochondrial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066982 (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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.21	Kd	622.1	nM	CHEMBL5653589
6.21	ED50	622.1	nM	CHEMBL5653589
6.17	Kd	676.9	nM	CHEMBL3752910
6.17	ED50	676.9	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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	2148789: Binding affinity to human MT-ATP6 incubated for 45 mins by Kinobead based pull down assay	kd	0.6221	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148789: Binding affinity to human MT-ATP6 incubated for 45 mins by Kinobead based pull down assay	kd	0.6769	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
enniatins	increases expression, decreases expression, affects cotreatment	5
Air Pollutants	decreases expression, increases abundance, increases mutagenesis	5
beauvericin	decreases expression, affects cotreatment, increases expression	3
Particulate Matter	increases mutagenesis, decreases expression, increases abundance	3
bisphenol A	decreases expression	2
Arsenic Trioxide	increases expression, decreases expression	2
Atrazine	decreases expression	2
Hydrogen Peroxide	decreases expression, increases expression	2
Plant Extracts	affects cotreatment, decreases expression, increases expression	2
Valproic Acid	decreases expression, decreases methylation, increases expression	2
1-Methyl-4-phenylpyridinium	decreases expression	2
aristolochic acid I	decreases expression	1
2-hydroxyestradiol	increases expression	1
di-n-octyl phthalate	decreases expression	1
tributyltin	increases response to substance	1
4-hydroxyestradiol	increases expression	1
methylparaben	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
ochratoxin A	affects cotreatment, increases expression, decreases expression	1
dimethoxyethyl phthalate	decreases expression	1
fialuridine	decreases expression	1
1-methyl-4-phenyl-2,3-dihydropyridinium	decreases expression	1
sarpogrelate	decreases expression, decreases reaction, increases reaction	1
azoxystrobin	decreases expression	1
bisphenol S	affects expression	1
MitoTEMPO	decreases expression, decreases reaction	1
regorafenib	affects expression	1
imeglimin	increases expression	1
Irinotecan	affects cotreatment, increases expression	1
Acetaminophen	affects cotreatment, 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
CHEMBL5651831	Binding	Binding affinity to human MT-ATP6 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

38 cell lines: 30 induced pluripotent stem cell, 6 finite cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_8A61	GM13411	Finite cell line	Male
CVCL_8A62	GM13740	Transformed cell line	Male
CVCL_8A63	GM13741	Transformed cell line	Male
CVCL_A2YS	GM28013	Finite cell line	Female
CVCL_A2YT	GM28014	Finite cell line	Female
CVCL_A4QJ	T8993G iPSC clone 1	Induced pluripotent stem cell	Male
CVCL_A4QK	T8993G iPSC clone 2	Induced pluripotent stem cell	Male
CVCL_A4QL	T8993G iPSC clone 3	Induced pluripotent stem cell	Male
CVCL_B7EN	TFA1.4	Induced pluripotent stem cell	Female
CVCL_B7EP	TDA2.3	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

128 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
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
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
NCT02176733	PHASE2	UNKNOWN	Trial of Cyclosporine in the Acute Phase of Leber Hereditary Optic Neuropathy
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)
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
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT03153293	PHASE2/PHASE3	UNKNOWN	A Single Intravitreal Injection of rAAV2-ND4 for the Treatment of Leber’s Hereditary Optic Neuropathy