Biology:MT-ATP8

Short description: Mitochondrial protein-coding gene whose product is involved in ATP synthesis

Generic protein structure example

Location of the MT-ATP8 gene in the human mitochondrial genome. MT-ATP8 is one of the two ATP synthase mitochondrial genes (red boxes).

The 46-nucleotide overlap in the reading frames of the human mitochondrial genes MT-ATP8 and MT-ATP6. For each nucleotide triplet (square brackets), the corresponding amino acid is given (one-letter code), either in the +1 frame for MT-ATP8 (in red) or in the +3 frame for MT-ATP6 (in blue).

ATP synthase protein 8 (metazoa)
Identifiers
Symbol	ATP-synt_8
Pfam	PF00895
Pfam clan	CL0255
InterPro	IPR001421
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Plant ATP synthase F0 subunit 8
Identifiers
Symbol	YMF19
Pfam	PF02326
Pfam clan	CL0255
InterPro	IPR003319
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Fungal ATP synthase protein 8 (A6L)
Identifiers
Symbol	Fun_ATP-synt_8
Pfam	PF05933
Pfam clan	CL0255
InterPro	IPR009230
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

MT-ATP8 (or ATP8) is a mitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 8' that encodes a subunit of mitochondrial ATP synthase, ATP synthase F_o subunit 8 (or subunit A6L). This subunit belongs to the F_o complex of the large, transmembrane F-type ATP synthase. This enzyme, which is also known as complex V, is responsible for the final step of oxidative phosphorylation in the electron transport chain. Specifically, one segment of ATP synthase allows positively charged ions, called protons, 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 called adenosine diphosphate (ADP) to ATP. Subunit 8 differs in sequence between Metazoa, plants and Fungi.

Structure

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. An unusual feature of the MT-ATP8 gene is its 46-nucleotide overlap with the MT-ATP6 gene. With respect to the reading frame (+1) of MT-ATP8, the MT-ATP6 gene starts on the +3 reading frame.

The MT-ATP8 protein weighs 8 kDa and is composed of 68 amino acids. The protein is a subunit of the F₁F_o 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 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 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. 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.

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 F_o (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 F_o unit of ATP synthase. 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 of E. coli homologue of this subunit was modeled based on electron microscopy data (chain M of PDB: 1c17​). 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 presents 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.

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. 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 to threonine as well as a change from tryptophan to arginine at position 55 of MT-ATP8. 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.

Further reading

• "Harvesting the fruit of the human mtDNA tree". Trends in Genetics 22 (6): 339–45. June 2006. doi:10.1016/j.tig.2006.04.001. PMID 16678300. 
• "Dinucleotide repeat in the human mitochondrial D-loop". Human Molecular Genetics 1 (2): 140. May 1992. doi:10.1093/hmg/1.2.140-a. PMID 1301157. 
• "Differentiation of HT-29 human colonic adenocarcinoma cells correlates with increased expression of mitochondrial RNA: effects of trehalose on cell growth and maturation". Cancer Research 52 (13): 3718–25. July 1992. PMID 1377597. 
• "Normal variants of human mitochondrial DNA and translation products: the building of a reference data base". Human Genetics 88 (2): 139–45. December 1991. doi:10.1007/bf00206061. PMID 1757091. 
• "Replication-competent human mitochondrial DNA lacking the heavy-strand promoter region". Molecular and Cellular Biology 11 (3): 1631–7. March 1991. doi:10.1128/MCB.11.3.1631. PMID 1996112. 
• "Seven unidentified reading frames of human mitochondrial DNA encode subunits of the respiratory chain NADH dehydrogenase". Cold Spring Harbor Symposia on Quantitative Biology 51 Pt 1 (1): 103–14. 1987. doi:10.1101/sqb.1986.051.01.013. PMID 3472707. 
• "URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit". Science 234 (4776): 614–8. October 1986. doi:10.1126/science.3764430. PMID 3764430. Bibcode: 1986Sci...234..614C. 
• "Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase". Nature 314 (6012): 592–7. 1985. doi:10.1038/314592a0. PMID 3921850. Bibcode: 1985Natur.314..592C. 
• "Sequence and organization of the human mitochondrial genome". Nature 290 (5806): 457–65. April 1981. doi:10.1038/290457a0. PMID 7219534. Bibcode: 1981Natur.290..457A. 
• "Distinctive features of the 5'-terminal sequences of the human mitochondrial mRNAs". Nature 290 (5806): 465–70. April 1981. doi:10.1038/290465a0. PMID 7219535. Bibcode: 1981Natur.290..465M. 
• "Recent African origin of modern humans revealed by complete sequences of hominoid mitochondrial DNAs". Proceedings of the National Academy of Sciences of the United States of America 92 (2): 532–6. January 1995. doi:10.1073/pnas.92.2.532. PMID 7530363. Bibcode: 1995PNAS...92..532H. 
• "Automating the identification of DNA variations using quality-based fluorescence re-sequencing: analysis of the human mitochondrial genome". Nucleic Acids Research 26 (4): 967–73. February 1998. doi:10.1093/nar/26.4.967. PMID 9461455. 
• "Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA". Nature Genetics 23 (2): 147. October 1999. doi:10.1038/13779. PMID 10508508. 
• "Mitochondrial genome variation and the origin of modern humans". Nature 408 (6813): 708–13. December 2000. doi:10.1038/35047064. PMID 11130070. Bibcode: 2000Natur.408..708I. 
• "Phylogenetic network for European mtDNA". American Journal of Human Genetics 68 (6): 1475–84. June 2001. doi:10.1086/320591. PMID 11349229. 
• "Major genomic mitochondrial lineages delineate early human expansions". BMC Genetics 2: 13. 2003. doi:10.1186/1471-2156-2-13. PMID 11553319. 
• "Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups". American Journal of Human Genetics 70 (5): 1152–71. May 2002. doi:10.1086/339933. PMID 11938495. 
• "Mitochondrial genome diversity of Native Americans supports a single early entry of founder populations into America". American Journal of Human Genetics 71 (1): 187–92. July 2002. doi:10.1086/341358. PMID 12022039. 
• "Natural selection shaped regional mtDNA variation in humans". Proceedings of the National Academy of Sciences of the United States of America 100 (1): 171–6. January 2003. doi:10.1073/pnas.0136972100. PMID 12509511. Bibcode: 2003PNAS..100..171M. 
• "Mitochondrial genome variation and evolutionary history of Australian and New Guinean aborigines". Genome Research 13 (7): 1600–6. July 2003. doi:10.1101/gr.686603. PMID 12840039. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

This article incorporates text from the public domain Pfam and InterPro: IPR001421