MT-ATP8

The ATP synthase protein 8 of human and other mammals is encoded in the mitochondrial genome by the MT-ATP8 gene. When the complete human mitochondrial genome was first published, the MT-ATP8 gene was described as the unidentified reading frame URF A6L. The protein is a subunit of the F1Fo ATPase, also known as Complex 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 Fo 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 Fo portion of the complex, comprising the proton 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. == Function ==

The MT-ATP8 gene encodes a subunit of mitochondrial ATP synthase, located within the thylakoid membrane and the inner mitochondrial membrane. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. This protein subunit appears to be an integral component of the stator stalk in yeast mitochondrial F-ATPases. The stator stalk is anchored in the membrane, 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 in Metazoa. == Nomenclature ==

The nomenclature 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 for oligomycin, a type of naturally-derived antibiotic that is able to inhibit the Fo unit of ATP synthase. 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, MT-ATP6 (or F6), and MT-ATP8 (or A6L). 3D structure of E. coli homologue of this subunit was modeled based on electron microscopy data (chain M of ). It forms a transmembrane 4-α-bundle. ==Clinical Significance==

Mutations to MT-ATP8 and other genes affecting oxidative phosphorylation in the mitochondria have been associated with a variety of neurodegenerative and cardiovascular disorders, including mitochondrial complex V deficiency, Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS), Leigh syndrome, and NARP syndrome. Most of the body's cells contain thousands of mitochondria, each with one or more copies of mitochondrial DNA. The severity of some mitochondrial disorders is associated with the percentage of mitochondria in each cell that has a particular genetic change. People with Leigh 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 of NARP 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. Mitochondrial complex V deficiency is a shortage (deficiency) or loss of function in complex V of the electron transport chain that can cause a wide variety of signs and symptoms affecting many organs and systems of the body, particularly the nervous system and the heart. 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), and developmental delay. They tend to develop elevated levels of lactic acid in the blood (lactic acidosis), which can cause nausea, vomiting, weakness, and rapid breathing. High levels of ammonia 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. 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 > C single-nucleotide polymorphisms at positions 8610 and 8614 that result in a homopolymeric cytosine stretch. Hypertrophic cardiomyopathy, a common feature of mitochondrial complex V deficiency, is characterized by thickening (hypertrophy) of the cardiac muscle that can lead to heart failure. 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 (downslanting palpebral fissures), a prominent bridge of the nose, low-set ears, thin lips, and a small chin (micrognathia). Infantile hypertrophic cardiomyopathy (CMHI) is also caused by mutations affecting distinct genetic loci, including MT-ATP6 and MT-ATP8. 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. == References ==