Thermogenin (called uncoupling protein by its discoverers and now known as uncoupling protein 1, or UCP1) [5] is a mitochondrial carrier protein found in brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis, and makes a quantitatively important contribution to countering heat loss in babies which would otherwise occur due to their high surface area-volume ratio.
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 and hence dissipating the proton gradient. 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 that permits the translocation of protons from the mitochondrial intermembrane space to the mitochondrial matrix. UCP1 is restricted to brown adipose tissue, 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. [6] Fatty acids are released by the following signaling cascade: Sympathetic nervous system terminals release Norepinephrine onto a Beta-3 adrenergic receptor on the plasma membrane. This activates adenylyl cyclase, which catalyses the conversion of ATP to cyclic AMP (cAMP). cAMP activates protein kinase A, causing its active C subunits to be freed from its regulatory R subunits. Active protein kinase A, in turn, phosphorylates triacylglycerol lipase, thereby activating it. The lipase converts triacylglycerols into free fatty acids, which activate UCP1, overriding the inhibition caused by purine nucleotides (GDP 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.
UCP1 is very similar to the ATP/ADP Carrier protein, or Adenine Nucleotide Translocator (ANT). [7] [8] The proposed alternating access model for UCP1 is based on the similar ANT mechanism. [9] The substrate comes in to the half open UCP1 protein from the cytoplasmic 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. 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 proteins, localized to the inner mitochondrial membrane, and they have a similar pattern of salt bridges, proline residues, and hydrophobic or aromatic amino acids that can close or open when in the cytoplasmic or matrix state. [7]
The atomic structure of human uncoupling protein 1 UCP1 has been solved by cryogenic-electron microscopy. [10] The structure has the typical fold of a member of the SLC25 family. [11] [12] UCP1 is locked in a cytoplasmic-open state by guanosine triphosphate in a pH-dependent manner, preventing proton leak. [10]
UCP1 is expressed in brown adipose tissue, which is functionally found only in eutherians. The UCP1, or thermogenin, gene likely arose in an ancestor of modern vertebrates, but did not initially allow for our vertebrate ancestor to use non-shivering thermogenesis for warmth. It wasn't until heat generation was adaptively selected for in placental mammal descendants of this common ancestor that UCP1 evolved its current function in brown adipose tissue to provide additional warmth. [13] 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, elephants, sea cows, whales and hyraxes) and lineages with low metabolic rates (e.g. pangolins, armadillos, sloths and anteaters). [14] Recent discoveries of non-heat-generating orthologues of UCP1 in fish and marsupials, 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. [15] 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. [16]
Researchers in the 1960s investigating brown adipose tissue, found that in addition to producing more heat than typical of other tissues, brown adipose tissue seemed to short circuit, or uncouple, respiration coupling. [17] Uncoupling protein 1 was discovered in 1976 by David G. Nicholls, Vibeke Bernson, and Gillian Heaton, and the discovery was published in 1978 and shown to be the protein responsible for this uncoupling effect. [18] UCP1 was later purified for the first time in 1980 and was first cloned in 1988. [19] [20]
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, and UCP5 (also known as BMCP1 or SLC25A14).
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. [21]
An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples this electron transfer with the transfer of protons (H+ ions) across a membrane. Many of the enzymes in the electron transport chain are embedded within the membrane.
Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue. Brown adipose tissue is found in almost all mammals.
Adipose tissue is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells such as adipose tissue macrophages. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body.
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, and the giant water lilies of the genus Victoria. The lodgepole pine dwarf mistletoe, Arceuthobium americanum, disperses its seeds explosively through thermogenesis.
The ERRs are orphan nuclear receptors, meaning the identity of their endogenous ligand has yet to be unambiguously determined. They are named because of sequence homology with estrogen receptors, but do not appear to bind estrogens or other tested steroid hormones.
Adenine nucleotide translocator (ANT), also known as the ADP/ATP translocase (ANT), ADP/ATP carrier protein (AAC) or mitochondrial ADP/ATP carrier, exchanges free ATP with free ADP across the inner mitochondrial membrane. ANT is the most abundant protein in the inner mitochondrial membrane and belongs to mitochondrial carrier family.
Mitochondrial carriers are proteins from solute carrier family 25 which transfer molecules across the membranes of the mitochondria. Mitochondrial carriers are also classified in the Transporter Classification Database. The Mitochondrial Carrier (MC) Superfamily has been expanded to include both the original Mitochondrial Carrier (MC) family and the Mitochondrial Inner/Outer Membrane Fusion (MMF) family.
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 the mitochondrial matrix to the mitochondrial intermembrane space. The energy lost in dissipating the proton gradient via UCPs is not used to do biochemical work. Instead, heat is generated. This is what links UCP to thermogenesis. However, not every type of UCPs are related to thermogenesis. Although UCP2 and UCP3 are closely related to UCP1, UCP2 and UCP3 do not affect thermoregulatory abilities of vertebrates. UCPs are positioned in the same membrane as the ATP synthase, which is also a proton channel. The two proteins thus work in parallel with one generating heat and the other generating ATP from ADP and inorganic phosphate, the last step in oxidative phosphorylation. Mitochondria respiration is coupled to ATP synthesis, but is regulated by UCPs. UCPs belong to the mitochondrial carrier (SLC25) family.
Mitochondrial uncoupling protein 2 is a protein that in humans is encoded by the UCP2 gene.
Mitochondrial uncoupling protein 3 is a protein that in humans is encoded by the UCP3 gene. The gene is located in chromosome (11q13.4) with an exon count of 7 and is expressed on the inner mitochondrial membrane. Uncoupling proteins transfer anions from the inner mitochondrial membrane to the outer mitochondrial membrane, thereby separating oxidative phosphorylation from synthesis of ATP, and dissipating energy stored in the mitochondrial membrane potential as heat. Uncoupling proteins also reduce generation of reactive oxygen species.
G-protein coupled receptor 3 is a protein that in humans is encoded by the GPR3 gene. The protein encoded by this gene is a member of the G protein-coupled receptor family of transmembrane receptors and is involved in signal transduction.
NAD-dependent deacetylase sirtuin-3, mitochondrial also known as SIRT3 is a protein that in humans is encoded by the SIRT3 gene [sirtuin 3 ]. SIRT3 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT3 exhibits NAD+-dependent deacetylase activity.
Brain mitochondrial carrier protein 1 is a protein that in humans is encoded by the SLC25A14 gene.
Mitochondrial uncoupling protein 4 is a protein that in humans is encoded by the SLC25A27 gene.
Tricarboxylate transport protein, mitochondrial, also known as tricarboxylate carrier protein and citrate transport protein (CTP), is a protein that in humans is encoded by the SLC25A1 gene. SLC25A1 belongs to the mitochondrial carrier gene family SLC25. High levels of the tricarboxylate transport protein are found in the liver, pancreas and kidney. Lower or no levels are present in the brain, heart, skeletal muscle, placenta and lung.
ADP/ATP translocase 4 (ANT4) is an enzyme that in humans is encoded by the SLC25A31 gene on chromosome 4. This enzyme inhibits apoptosis by catalyzing ADP/ATP exchange across the mitochondrial membranes and regulating membrane potential. In particular, ANT4 is essential to spermatogenesis, as it imports ATP into sperm mitochondria to support their development and survival. Outside this role, the SLC25AC31 gene has not been implicated in any human disease.
ADP/ATP translocase 2 is a protein that in humans is encoded by the SLC25A5 gene on the X chromosome.
Daniel Ricquier, is a French biochemist known for his work in mitochondria and hereditary metabolic diseases. Ricquier has been a member of the French Academy of Sciences since 2002, and a professor of biochemistry and Molecular Biology at the Faculty of Medicine of the University of Paris Descartes since 2003.
Antonio Vidal-Puig is a Spanish medical doctor and scientist who works as a Professor of Molecular Nutrition and Metabolism at the University of Cambridge (UK), best known for advancing the concept that pharmacological targeting of brown fat may serve to treat overweight and obesity in affected individuals, as well as for introducing the concept of adipose tissue "expandability" as an important factor in the pathogenesis of insulin resistance in the context of positive energy balance. His published work focuses on areas such as adipose tissue metabolism and lipotoxicity, regulation of insulin secretion, and the pathophysiology of metabolic syndrome, obesity, and type 2 diabetes.
Barbara Cannon is a British-Swedish biochemist, physiologist and an academic. She is an emeritus professor at Stockholm University as well as the chairman of the scientific advisory board at The Helmholtz Centre. She is also a consultant at Combigene.
