Thermogenin (called
uncoupling protein
An uncoupling protein (UCP) is a mitochondrial inner membrane protein that is a regulated proton channel or transporter. An uncoupling protein is thus capable of dissipating the proton gradient generated by NADH-powered pumping of protons from th ...
by its discoverers and now known as uncoupling protein 1, or UCP1)
is a
mitochondrial carrier
Mitochondrial carriers are proteins from solute carrier family 25 which transfer molecules across the membranes of the mitochondria. Mitochondrial carriers are also classified in thTransporter Classification Database The Mitochondrial Carrier (M ...
protein found in
brown adipose tissue
Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (or white fat). Brown adipose tissue is found in almost all mammals.
Classification of brown fat refers to two distinct cell populations with si ...
(BAT). It is used to generate heat by non-shivering
thermogenesis
Thermogenesis is the process of heat production in organisms. It occurs in all warm-blooded animals, and also in a few species of thermogenic plants such as the Eastern skunk cabbage, the Voodoo lily (''Sauromatum venosum''), and the giant wate ...
, and makes a quantitatively important contribution to countering heat loss in babies which would otherwise occur due to their high surface area-volume ratio.
Mechanism
![ThermogeneseAdipozyten-en](https://upload.wikimedia.org/wikipedia/commons/6/68/ThermogeneseAdipozyten-en.svg)
UCP1 belongs to the UCP family which are transmembrane proteins that decrease the proton gradient generated in oxidative phosphorylation. They do this by increasing the permeability of the inner mitochondrial membrane, allowing protons that have been pumped into the intermembrane space to return to the mitochondrial matrix. UCP1-mediated heat generation in brown fat uncouples the respiratory chain, allowing for fast substrate oxidation with a low rate of ATP production. UCP1 is related to other mitochondrial metabolite transporters such as the adenine nucleotide translocator, a proton channel in the
mitochondrial inner membrane
The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space.
Structure
The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. ...
that permits the translocation of protons from the mitochondrial
intermembrane space to the
mitochondrial matrix
In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribo ...
. UCP1 is restricted to
brown adipose tissue
Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (or white fat). Brown adipose tissue is found in almost all mammals.
Classification of brown fat refers to two distinct cell populations with si ...
, where it provides a mechanism for the enormous heat-generating capacity of the tissue.
UCP1 is activated in the brown fat cell by fatty acids and inhibited by nucleotides. Fatty acids are released by the following signaling cascade: Sympathetic nervous system terminals release
Norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
onto a
Beta-3 adrenergic receptor
The beta-3 adrenergic receptor (β3-adrenoceptor), also known as ADRB3, is a beta-adrenergic receptor, and also denotes the human gene encoding it.
Function
Actions of the β3 receptor include
*Enhancement of lipolysis in adipose tissue.
*Ther ...
on the
plasma membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
. This activates
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
, which catalyses the conversion of ATP to
cyclic AMP
Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
(cAMP). cAMP activates
protein kinase A
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
, causing its active C subunits to be freed from its regulatory R subunits. Active protein kinase A, in turn, phosphorylates
triacylglycerol lipase
The enzyme Triacylglycerol lipase (also Triglyceride lipase, EC 3.1.1.3;systematic name triacylglycerol acylhydrolase) catalyses the hydrolysis of ester linkages of triglycerides:
: triacylglycerol + H2O diacylglycerol + a carboxylate
These l ...
, thereby activating it. The lipase converts triacylglycerols into free fatty acids, which activate UCP1, overriding the inhibition caused by purine nucleotides (
GDP
Gross domestic product (GDP) is a monetary measure of the market value of all the final goods and services produced and sold (not resold) in a specific time period by countries. Due to its complex and subjective nature this measure is often ...
and
ADP). During the termination of thermogenesis, thermogenin is inactivated and residual fatty acids are disposed of through oxidation, allowing the cell to resume its normal energy-conserving state.
![The Alternating Access Model for UCP1 with H+ as a Substrate](https://upload.wikimedia.org/wikipedia/commons/f/fd/The_Alternating_Access_Model_for_UCP1_with_H%2B_as_a_Substrate.jpg)
UCP1 is very similar to the ATP/ADP Carrier protein, or Adenine Nucleotide Translocator (
ANT
Ants are eusocial insects of the family Formicidae and, along with the related wasps and bees, belong to the order Hymenoptera. Ants evolved from vespoid wasp ancestors in the Cretaceous period. More than 13,800 of an estimated total of 22 ...
).
The proposed alternating access model for UCP1 is based on the similar ANT mechanism. The
substrate comes in to the half open UCP1 protein from the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
ic side of the membrane, the protein closes the cytoplasmic side so the substrate is enclosed in the protein, and then the matrix side of the protein opens, allowing the substrate to be released into the
mitochondrial matrix
In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribo ...
. The opening and closing of the protein is accomplished by the tightening and loosening of
salt bridges at the membrane surface of the protein. Substantiation for this modelling of UCP1 on ANT is found in the many conserved residues between the two proteins that are actively involved in the transportation of substrate across the membrane. Both proteins are
integral membrane protein
An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a signi ...
s, localized to the inner mitochondrial membrane, and they have a similar pattern of salt bridges,
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
residues, and
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, th ...
or
aromatic
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
amino acids that can close or open when in the cytoplasmic or matrix state.
Evolution
UCP1 is expressed in brown adipose tissue, which is functionally found only in
eutheria
Eutheria (; from Greek , 'good, right' and , 'beast'; ) is the clade consisting of all therian mammals that are more closely related to placentals than to marsupials.
Eutherians are distinguished from noneutherians by various phenotypic tra ...
ns. The UCP1, or thermogenin, gene likely arose in an ancestor of modern
vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
s, but did not initially allow for our vertebrate ancestor to use non-shivering
thermogenesis
Thermogenesis is the process of heat production in organisms. It occurs in all warm-blooded animals, and also in a few species of thermogenic plants such as the Eastern skunk cabbage, the Voodoo lily (''Sauromatum venosum''), and the giant wate ...
for warmth. It wasn't until heat generation was
adaptively selected for in
placental
Placental mammals (infraclass Placentalia ) are one of the three extant subdivisions of the class Mammalia, the other two being Monotremata and Marsupial
Marsupials are any members of the mammalian infraclass Marsupialia. All extant marsup ...
mammal descendants of this common ancestor that UCP1 evolved its current function in brown adipose tissue to provide additional warmth. While UCP1 plays a key thermogenic role in wide range placental mammals, particularly those with small body size and those that hibernate, the UCP1 gene has lost functionality in several large-bodied lineages (e.g.
horses
The horse (''Equus ferus caballus'') is a domesticated, one-toed, hoofed mammal. It belongs to the taxonomic family Equidae and is one of two extant subspecies of ''Equus ferus''. The horse has evolved over the past 45 to 55 million yea ...
,
elephants
Elephants are the largest existing land animals. Three living species are currently recognised: the African bush elephant, the African forest elephant, and the Asian elephant. They are the only surviving members of the family Elephantidae and ...
,
sea cows,
whales
Whales are a widely distributed and diverse group of fully aquatic placental marine mammals. As an informal and colloquial grouping, they correspond to large members of the infraorder Cetacea, i.e. all cetaceans apart from dolphins and ...
and
hyraxes
Hyraxes (), also called dassies, are small, thickset, herbivorous mammals in the order Hyracoidea. Hyraxes are well-furred, rotund animals with short tails. Typically, they measure between long and weigh between . They are superficially simil ...
) and lineages with low metabolic rates (e.g.
pangolins
Pangolins, sometimes known as scaly anteaters, are mammals of the order Pholidota (, from Ancient Greek ϕολιδωτός – "clad in scales"). The one extant family, the Manidae, has three genera: ''Manis'', ''Phataginus'', and ''Smutsia'' ...
,
armadillos
Armadillos (meaning "little armored ones" in Spanish) are New World placental mammals in the order Cingulata. The Chlamyphoridae and Dasypodidae are the only surviving families in the order, which is part of the superorder Xenarthra, along w ...
,
sloths and anteaters). Recent discoveries of non-heat-generating
orthologues
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...
of UCP1 in fish and
marsupial
Marsupials are any members of the mammalian infraclass Marsupialia. All extant marsupials are endemic to Australasia, Wallacea and the Americas. A distinctive characteristic common to most of these species is that the young are carried in a po ...
s, other descendants of the ancestor of modern vertebrates, show that this gene was passed on to all modern vertebrates, but aside from placental mammals, none have heat producing capability. This further suggests that UCP1 had a different original purpose and in fact phylogenetic and sequence analyses indicate that UCP1 is likely a mutated form of a
dicarboxylate carrier protein that adapted for thermogenesis in placental mammals.
History
Researchers in the 1960s investigating
brown adipose tissue
Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (or white fat). Brown adipose tissue is found in almost all mammals.
Classification of brown fat refers to two distinct cell populations with si ...
, found that in addition to producing more heat than typical of other tissues, brown adipose tissue seemed to short circuit, or uncouple, respiration coupling. Uncoupling protein 1 was discovered in 1976 by David Nicholls, Vibeke Bernson, and Gillian Heaton, and the discovery was published in 1978 and shown to be the protein responsible for this uncoupling effect.
UCP1 was later purified for the first time in 1980 and was first cloned in 1988.
Uncoupling protein two (UCP2), a homolog of UCP1, was identified in 1997. UCP2 localizes to a wide variety of tissues, and is thought to be involved in regulating reactive oxygen species (ROS). In the past decade, three additional homologs of UCP1 have been identified, including
UCP3,
UCP4
Mitochondrial uncoupling protein 4 is a protein that in humans is encoded by the ''SLC25A27'' gene.
Mitochondrial uncoupling proteins (UCP) are members of the larger family of mitochondrial anion carrier proteins (MACP). UCPs separate oxidative p ...
, and
UCP5 (also known as BMCP1 or SLC25A14).
Clinical relevance
Methods of delivering UCP1 to cells by gene transfer therapy or methods of its upregulation have been an important line of enquiry in research into the treatment of obesity, due to their ability to dissipate excess metabolic stores.
See also
*
2,4-Dinitrophenol
2,4-Dinitrophenol (2,4-DNP or simply DNP) is an organic compound with the formula HOC6H3(NO2)2. It is a yellow, crystalline solid that has a sweet, musty odor. It sublimates, is volatile with steam, and is soluble in most organic solvents as well ...
(A synthetic
small-molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...
proton shuttle with similar effects)
References
Further reading
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External links
Seaweed anti-obesity tablet hope(BBC - Thermogenin mentioned as part of process)
* {{MeshName, thermogenin
Cellular respiration
Mitochondria