| ATP6 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | ATP6, ATPase6, MTATP synthase Fo subunit 6 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:516060;MGI:99927;HomoloGene:5012;GeneCards:ATP6;OMA:ATP6 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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MT-ATP6 (orATP6) is amitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 6' that encodes theATP synthase Fo subunit 6 (orsubunit/chain A). This subunit belongs to the Fo 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.Mutations in theMT-ATP6 gene have been found in approximately 10 to 20 percent of people withLeigh syndrome.[6]
TheMT-ATP6 gene provides information for making a protein that is essential for normal mitochondrial function. The humanMT-ATP6 gene, located inmitochondrial DNA, is 681base pairs in length.[7] An unusual feature ofMT-ATP6 is the 46-nucleotidegene overlap of its firstcodons with the end of theMT-ATP8 gene. With respect to theMT-ATP6 reading frame (+3), theMT-ATP8 gene ends in the +1 reading frame with a TAGstop codon.
The MT-ATP6 protein weighs 24.8 kDa and is composed of 226amino acids.[8][9] The protein is a subunit of the F1Fo ATPase, also known asComplex V, which consists of 14 nuclear- and 2 mitochondrial-encoded subunits. As an A subunit, MT-ATP6 is contained within the non-catalytic,transmembrane Fo portion of the complex.[7]
Thenomenclature of the enzyme has a long history. The F1 fraction derives its name from the term "Fraction 1" and Fo (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 Fo unit of ATP synthase.[10][11] The Fo 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, F6, and8 (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.
This subunit is a key component of the proton channel, and may play a direct role in the translocation of protons across the membrane. Catalysis in the F1 complex depends upon the rotation of the central stalk and Fo c-ring, which in turn is driven by the flux of protons through the membrane via the interface between the F0 c-ring and subunit A. The peripheral stalk links subunit A to the external surface of the F1 domain, and is thought to act as a stator to counter the tendency of subunit A and the F1alpha3 beta3 catalytic portion to rotate with the central rotary element.[12]
Mutations to MT-ATP6 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 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.[13]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.[14]
Another common feature of mitochondrial complex V deficiency ishypertrophic cardiomyopathy. This condition is characterized by thickening (hypertrophy) of thecardiac muscle that can lead toheart failure.[13] The m.8528T>C mutation occurs in the overlapping region of the MT-ATP6 andMT-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 ofMT-ATP8.[15][16] 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).[13]
Pathogenic variants of the mitochondrial gene MT-ATP6 are known to cause mtDNA-associatedLeigh syndrome, a progressive brain disorder that usually appears in infancy or early childhood. Affected children may experiencedelayed development, muscle weakness, problems with movement, or difficulty breathing.[6] Other variants known to cause mtDNA-associated Leigh syndrome involveMT-TL1,MT-TK,MT-TW,MT-TV,MT-ND1,MT-ND2,MT-ND3,MT-ND4,MT-ND5,MT-ND6 andMT-CO3. Abnormalities in mitochondrial energy generation result in neurodegenerative disorders likeLeigh syndrome, which is characterized by an onset of symptoms between 12 months and three years of age. The symptoms frequently present themselves following aviral infection and include movement disorders andperipheral neuropathy, as well ashypotonia,spasticity andcerebellar ataxia. Roughly half of affected patients die ofrespiratory orcardiac failure by the age of three.Leigh syndrome is a maternally inherited disorder and its diagnosis is established throughgenetic testing of the aforementioned mitochondrial genes, including MT-ATP6.[17] MT-ATP6 gene mutations associated with Leigh syndrome change one DNA building block (nucleotide) in the MT-ATP6 gene. The most common genetic change replaces the nucleotidethymine withguanine at position 8993 (written as T8993G). The mutations that causeLeigh syndrome impair the function or stability of theATP synthase complex, inhibitingATP production and impairingoxidative phosphorylation. Although the exact mechanism is unclear, researchers believe that impaired oxidative phosphorylation can lead tocell death because of decreased energy available in the cell. Certain tissues that require large amounts of energy, such as the brain, muscles, and heart, seem especially sensitive to decreases in cellular energy. Cell death in the brain likely causes the characteristic changes in the brain seen in Leigh syndrome, which contribute to the signs and symptoms of the condition. Cell death in other sensitive tissues may also contribute to the features of Leigh syndrome. Aheteroplasmic T→C MT-ATP6 mutation at position 9185 results in the substitution of a highly conservedleucine toproline atcodon 220 and aheteroplasmic T→Cmissense mutation at position 9191 converted a highly conservedleucine to aproline at position 222 of thepolypeptide, leading to a Leigh-typephenotype. The T9185C mutation resulted in a mild and reversiblephenotype, with 97% of the patient's muscle and blood samples reflecting the mutation. The T9191C mutation presented a much more severe phenotype that resulted in the death of the patient at 2 years of age.[18]
Some of the mutations of the ATP6 gene that cause Leigh syndrome are also responsible for a similar, but less severe, condition calledneuropathy, ataxia, and retinitis pigmentosa (NARP).[19] A small number of mutations in the MT-ATP6 gene have been identified in people with NARP. Each of these mutations changes onenucleotide in the MT-ATP6 gene. As in Leigh syndrome, the most common genetic change associated with NARP replaces thenucleotidethymine withguanine at position 8993 (written as T8993G). The mutations that cause NARP alter the structure or function ofATP synthase, reducing the ability of mitochondria to produce ATP. Although the precise effects of these mutations are unclear, researchers continue to investigate how changes in the MT-ATP6 gene interfere with ATP production and lead to muscle weakness, vision loss, and the other features of NARP.[6]
A condition called familial bilateral striatal necrosis, which is similar to Leigh syndrome, can also result from changes in the MT-ATP6 gene. In the few reported cases with these mutations, affected children have had delayed development, problems with movement and coordination, weak muscle tone (hypotonia), and an unusually small head size (microcephaly). Researchers have not determined why MT-ATP6 mutations result in this combination of signs and symptoms in children with bilateral striatal necrosis.[6]
MT-ATP6 has been shown to have 20 binaryprotein-protein interactions including 17 co-complex interactions. MT-ATP6 appears to interact withSP1.[20]
TheSENS Research Foundation have published a paper detailing the successfulallotopic expression of replacement DNA for the MT-ATP6 gene in the cell nuclear DNA.[21]
This article incorporates text from this source, which is in thepublic domain.This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
