ATP8
Identifiers
Aliases	ATP8, ATPase8, MTMT-ATP synthase F0 subunit 8
External IDs	OMIM:516070;MGI:99926;HomoloGene:124425;GeneCards:ATP8;OMA:ATP8 - orthologs
Gene location (Human) Chr. Mitochondrial DNA (human)[1] Band n/a Start 8,366bp[1] End 8,572bp[1]
Gene location (Mouse) Chr. Mitochondrial DNA (mouse)[2] Band n/a Start 7,766bp[2] End 7,969bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right hemisphere of cerebellum right lung Descending thoracic aorta gastrocnemius muscle right ovary olfactory zone of nasal mucosa right adrenal cortex superior frontal gyrus subcutaneous adipose tissue left adrenal gland Top expressed in striatum of neuraxis ventricular zone ganglionic eminence Hypothalamus neural tube urinary bladder dentate gyrus of hippocampal formation granule cell white adipose tissue adrenal gland zone of skin More reference expression data BioGPS n/a
Gene ontology Molecular function ATPase activity transmembrane transporter activity proton transmembrane transporter activity Cellular component integral component of membrane mitochondrial inner membrane mitochondrial proton-transporting ATP synthase complex, coupling factor F(o) mitochondrion membrane mitochondrial membranes proton-transporting ATP synthase complex, coupling factor F(o) mitochondrial proton-transporting ATP synthase complex Biological process mitochondrial ATP synthesis coupled proton transport ATP synthesis coupled proton transport ion transport ATP biosynthetic process cristae formation Sources:Amigo /QuickGO
Orthologs Species Human Mouse Entrez 4509 17706 Ensembl ENSG00000228253 ENSMUSG00000064356 UniProt P03928 P03930 RefSeq (mRNA) n/a n/a RefSeq (protein) n/a NP_904332 Location (UCSC) Chr M: 0.01 – 0.01 Mb Chr M: 0.01 – 0.01 Mb PubMed search [3] [4]
Wikidata
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MT-ATP8 (orATP8) is amitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 8' that encodes a subunit ofmitochondrial ATP synthase,ATP synthase F_o subunit 8 (orsubunit A6L). This subunit belongs to the F_o complex of the large, transmembrane F-typeATP synthase.^[5] This enzyme, which is also known as complex V, is responsible for the final step ofoxidative phosphorylation in theelectron transport chain. Specifically, one segment of ATP synthase allows positively chargedions, calledprotons, to flow across a specialized membrane inside mitochondria. Another segment of the enzyme uses the energy created by this proton flow to convert a molecule calledadenosine diphosphate (ADP) toATP.^[6] Subunit 8 differs insequence betweenMetazoa,plants andFungi.

The ATP synthase protein 8 of human and other mammals is encoded in themitochondrial genome by theMT-ATP8gene. When the complete human mitochondrial genome was first published, theMT-ATP8 gene was described as the unidentifiedreading frameURF A6L.^[5] An unusual feature of theMT-ATP8 gene is its 46-nucleotide overlap with theMT-ATP6 gene. With respect to the reading frame (+1) ofMT-ATP8, theMT-ATP6 gene starts on the +3 reading frame.

The MT-ATP8 protein weighs 8 kDa and is composed of 68amino acids.^[7][8] The protein is a subunit of the F₁F_o ATPase, also known asComplex V, which consists of 14 nuclear- and 2 mitochondrial-encoded subunits. F-type ATPases consist of two structural domains, F₁ containing the extramembraneous catalytic core and F_o containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. As an A subunit, MT-ATP8 is contained within the non-catalytic,transmembrane F_o portion of the complex, comprising theproton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and a single representative of the other 3. The proton channel consists of three main subunits (a, b, c). This gene encodes the delta subunit of the catalytic core. Alternatively spliced transcript variants encoding the same isoform have been identified.^[9][6]

The MT-ATP8gene encodes a subunit of mitochondrialATP synthase, located within thethylakoid membrane and theinner mitochondrial membrane. Mitochondrial ATP synthasecatalyzes ATP synthesis, utilizing anelectrochemical gradient ofprotons across the inner membrane duringoxidative phosphorylation.^[9] The F_o region causes rotation of F₁, which has a water-soluble component that hydrolyzes ATP and together, the F₁F_o creates a pathway for movement of protons across the membrane.^[10]

Thisprotein subunit appears to be an integral component of the stator stalk inyeastmitochondrialF-ATPases.^[11] The stator stalk is anchored in themembrane, and acts to prevent futile rotation of the ATPase subunits relative to the rotor during coupled ATP synthesis/hydrolysis. This subunit may have an analogous function inMetazoa.

Thenomenclature of the enzyme has a long history. The F₁ fraction derives its name from the term "Fraction 1" and F_o (written as a subscript letter "o", not "zero") derives its name from being the binding fraction foroligomycin, a type of naturally-derived antibiotic that is able to inhibit the F_o unit of ATP synthase.^[12][13] The F_o region of ATP synthase is a proton pore that is embedded in the mitochondrial membrane. It consists of three main subunits A, B, and C, and (in humans) six additional subunits,d,e,f,g,MT-ATP6 (or F6), and MT-ATP8 (or A6L). 3D structure ofE. coli homologue of this subunit was modeled based onelectron microscopy data (chain M ofPDB:1c17​). It forms a transmembrane 4-α-bundle.

Mutations to MT-ATP8 and other genes affectingoxidative phosphorylation in the mitochondria have been associated with a variety ofneurodegenerative andcardiovascular disorders, including mitochondrial complex V deficiency,Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS),Leigh syndrome, andNARP syndrome. Most of the body's cells contain thousands of mitochondria, each with one or more copies ofmitochondrial DNA. The severity of somemitochondrial disorders is associated with the percentage of mitochondria in each cell that has a particular genetic change. People withLeigh syndrome due to a MT-ATP6 gene mutation tend to have a very high percentage of mitochondria with the mutation (from more than 90 percent to 95 percent). The less-severe features ofNARP result from a lower percentage of mitochondria with the mutation, typically 70 percent to 90 percent. Because these two conditions result from the same genetic changes and can occur in different members of a single family, researchers believe that they may represent a spectrum of overlapping features instead of two distinct syndromes.^[6]

Mitochondrial complex V deficiency presents with heterogeneous clinical manifestations includingneuropathy,ataxia,hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy can present with negligible to extremehypertrophy, minimal to extensivefibrosis andmyocyte disarray, absent to severe left ventricular outflow tract obstruction, and distinct septal contours/morphologies with extremely varying clinical course.^[14][15]

Mitochondrial complex V deficiency is a shortage (deficiency) or loss of function incomplex V of theelectron transport chain that can cause a wide variety ofsigns and symptoms affecting many organs and systems of the body, particularly thenervous system and theheart. The disorder can be life-threatening in infancy or early childhood. Affected individuals may have feeding problems, slow growth, low muscle tone (hypotonia), extreme fatigue (lethargy), anddevelopmental delay. They tend to develop elevated levels oflactic acid in the blood (lactic acidosis), which can cause nausea, vomiting, weakness, and rapid breathing. High levels ofammonia in the blood (hyperammonemia) can also occur in affected individuals, and in some cases result in abnormal brain function (encephalopathy) and damage to other organs.^[16]Ataxia,microcephaly, developmental delay and intellectual disability have been observed in patients with a frameshift mutation in MT-ATP6. This causes a C insertion at position 8612 that results in a truncated protein only 36 amino acids long, and two T > Csingle-nucleotide polymorphisms at positions 8610 and 8614 that result in a homopolymericcytosine stretch.^[17]

Hypertrophic cardiomyopathy, a common feature of mitochondrial complex V deficiency, is characterized by thickening (hypertrophy) of thecardiac muscle that can lead toheart failure.^[16] The m.8528T>C mutation occurs in the overlapping region of the MT-ATP6 and MT-ATP8 genes and has been described in multiple patients with infantile cardiomyopathy. This mutation changes the initiation codon in MT-ATP6 tothreonine as well as a change fromtryptophan toarginine at position 55 of MT-ATP8.^[18][15] Individuals with mitochondrial complex V deficiency may also have a characteristic pattern of facial features, including a high forehead, curved eyebrows, outside corners of the eyes that point downward (downslantingpalpebral fissures), a prominent bridge of the nose, low-set ears, thin lips, and a small chin (micrognathia).^[16]

Infantile hypertrophic cardiomyopathy (CMHI) is also caused by mutations affecting distinctgenetic loci, includingMT-ATP6 and MT-ATP8. An infantile form ofhypertrophic cardiomyopathy, a heart disorder characterized byventricular hypertrophy, which is usually asymmetric and often involves theinterventricular septum. The symptoms includedyspnea,syncope, collapse,palpitations, andchest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk ofcardiac failure andsudden cardiac death.^[14][15]

This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.

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