ATP synthase F1 subunit alpha, mitochondrial is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in humans is encoded by the ''ATP5F1A''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Function
This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, using an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F
1, and the membrane-spanning component, F
o, 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 alpha subunit of the catalytic core. Alternatively spliced transcript variants encoding the same protein have been identified. Pseudogenes of this gene are located on chromosomes 9, 2, and 16.
Structure
The ''ATP5F1A'' gene, located on the q arm of
chromosome 18
Chromosome 18 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 18 spans about 80 million base pairs (the building material of DNA) and represents about 2.5 percent of the total DNA in ...
in position 21, is made up of 13 exons and is 20,090 base pairs in length.
The ATP5F1A protein weighs 59.7 kDa and is composed of 553 amino acids.
The protein is a subunit of the catalytic portion of the F
1F
o ATPase, also known as
Complex V
ATP synthase is a protein that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). It is classified under ligases as it changes ADP by the formation o ...
, which consists of 14 nuclear and 2 mitochondrial -encoded subunits. As an alpha subunit, ATP5F1A is contained within the catalytic F
1 portion of the complex.
The
nomenclature
Nomenclature (, ) is a system of names or terms, or the rules for forming these terms in a particular field of arts or sciences. The principles of naming vary from the relatively informal naming conventions, conventions of everyday speech to the i ...
of the enzyme has a long history. The F
1 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
Oligomycins are macrolides created by ''Streptomyces'' that can be poisonous to other organisms.
Function
They have use as antibiotics.
Oligomycin A is an inhibitor of ATP synthase. In oxidative phosphorylation research, it is used to prevent ...
, a type of naturally-derived antibiotic that is able to inhibit the F
o unit of ATP synthase.
The F
1 particle is large and can be seen in the transmission electron microscope by negative staining.
These are particles of 9 nm diameter that pepper the inner mitochondrial membrane. They were originally called elementary particles and were thought to contain the entire respiratory apparatus of the mitochondrion, but, through a long series of experiments,
Efraim Racker
Efraim Racker (June 28, 1913 – September 9, 1991) was an Austrian biochemist who was responsible for identifying and purifying Factor 1 (F1), the first part of the ATP synthase enzyme to be characterised. F1 is only a part of a larger ATP syn ...
and his colleagues (who first isolated the F
1 particle in 1961) were able to show that this particle is correlated with ATPase activity in uncoupled mitochondria and with the ATPase activity in
submitochondrial particle
A submitochondrial particle (SMP) is an artificial vesicle made from the inner mitochondrial membrane. They can be formed by subjecting isolated mitochondria to sonication, freezing and thawing, high pressure, or osmotic shock. SMPs can be used to ...
s created by exposing mitochondria to ultrasound. This ATPase activity was further associated with the creation of ATP by a long series of experiments in many laboratories.
Function
Mitochondrial membrane ATP synthase (F
1F
o ATP synthase or
Complex V
ATP synthase is a protein that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). It is classified under ligases as it changes ADP by the formation o ...
) 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. F-type ATPases consist of two structural domains, F
1 - containing the extramembraneous catalytic core, and F
o - containing the membrane proton channel, linked together by a central stalk and a 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. Subunits alpha and beta form the catalytic core in F
1. Rotation of the central stalk against the surrounding alpha(3)beta(3) subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits. Subunit alpha does not bear the catalytic high-affinity ATP-binding sites.
Clinical significance
Mutations affecting the ATP5F1A gene cause combined oxidative phosphorylation deficiency 22 (COXPD22), a mitochondrial disorder characterized by intrauterine growth retardation,
microcephaly
Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it ...
,
hypotonia
Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...
,
pulmonary hypertension, failure to thrive,
encephalopathy
Encephalopathy (; from grc, ἐνκέφαλος "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but r ...
, and
heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
. Mutations on the ATP5F1A gene also cause mitochondrial complex V deficiency, nuclear 4 (MC5DN4), a
mitochondrial disorder
Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of ...
with heterogeneous clinical manifestations including dysmorphic features, psychomotor retardation,
hypotonia
Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...
, growth retardation,
cardiomyopathy
Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...
, enlarged liver,
hypoplastic kidneys and elevated lactate levels in urine, plasma and cerebrospinal fluid.
Resveratrol
Resveratrol (3,5,4′-trihydroxy-''trans''-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacteria or fungi. Sources ...
inhibition of the F1 catalytic core increases
adenosine monophosphate
Adenosine monophosphate (AMP), also known as 5'-adenylic acid, is a nucleotide. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine; it is an ester of phosphoric acid and the nucleoside adenosine. As a substituent it t ...
(AMP) levels, thereby activating the
AMP-activated protein kinase
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cell ...
enzyme.
Model organisms
Model organism
A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workin ...
s have been used in the study of ATP5F1A function. A conditional
knockout mouse
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
line, called ''Atp5a1
tm1a(EUCOMM)Wtsi''
was generated as part of the
International Knockout Mouse Consortium
The International Knockout Mouse Consortium (IKMC) is a scientific endeavour to produce a collection of mouse embryonic stem cell lines that together lack every gene in the genome, and then to distribute the cells to scientific researchers to crea ...
program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized
phenotypic screen
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
to determine the effects of deletion.
Twenty two tests were carried out on
mutant
In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...
mice and five significant abnormalities were observed.
No
homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
mutant
In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...
embryos were identified during gestation, and therefore none survived until
weaning
Weaning is the process of gradually introducing an infant human or another mammal to what will be its adult diet while withdrawing the supply of its mother's milk.
The process takes place only in mammals, as only mammals produce milk. The infan ...
. The remaining tests were carried out on
heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
mutant adult mice and decreased body weight, lean body mass and
hypoproteinemia
Hypoproteinemia is a condition where there is an abnormally low level of protein in the blood. There are several causes that all result in edema once serum protein levels fall below a certain threshold.
Causes
# Nutritional hypoproteinemia is due ...
was observed in female animals.
References
Further reading
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External links
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{{PDB Gallery, geneid=498
Genes mutated in mice