Brown adipose tissue (BAT) and brown in white (brite) adipose tissue, termed also beige adipose tissue, are major sites of mammalian nonshivering thermogenesis. Mitochondrial uncoupling protein 1 (UCP1), specific for these tissues, is the key factor for heat production. Recent molecular aspects of UCP1 structure provide support for the fatty acid cycling model of coupling, i.e. when UCP1 expels fatty acid anions in a uniport mode from the matrix, while uncoupling. Protonophoretic function is ensured by return of the protonated fatty acid to the matrix independent of UCP1. This mechanism is advantageous for mitochondrial uncoupling and compatible with heat production in a pro-thermogenic environment, such as BAT. It must still be verified whether posttranslational modification of UCP1, such as sulfenylation of Cys253, linked to redox activity, promotes UCP1 activity. BAT biogenesis and UCP1 expression, has also been linked to the pro-oxidant state of mitochondria, further endorsing a redox signalling link promoting an establishment of pro-thermogenic state. We discuss circumstances under which promotion of superoxide formation exceeds its attenuation by uncoupling in mitochondria and throughout point out areas of future research into UCP1 function.
- MeSH
- Adipose Tissue, Brown chemistry MeSH
- Humans MeSH
- Mitochondrial Proteins metabolism MeSH
- Oxidation-Reduction MeSH
- Protein Processing, Post-Translational MeSH
- Thermogenesis * MeSH
- Uncoupling Protein 1 metabolism physiology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Uncoupling proteiny jsou mitochondriální bílkoviny odpřahující tvorbu ATP od dýchacího řetězce. Dosud jich bylo objeveno několik, nejvíce prozkoumán je UCP1. Je exprimován v hnědé tukové tkáni a jeho funkcí je tvorba tepla. Termogenní funkce této tkáně je známa již delší dobu, u člověka však hnědý tuk obvykle zaniká již v dětství. V dospělosti v lidském organizmu najdeme UCP2 a UCP3. Předpokládá se, že tyto bílkoviny ovlivňují metabolizmus lipidů a energetický výdej, proto se zkoumá jejich možné využití v terapii obezity. Přesná fyziologická funkce v organizmu však dosud nebyla vysvětlena.
Uncoupling proteins are located in the inner mitochondria membrane. Their name is derived from their function: they uncouple oxidative processes of the respiratory chain from ATP synthesis. Hitherto several members of the family have been described, the best known being UCP1. UCP1 can be expressed exclusively in brown adipose tissue and it is responsible for the heat production. In humans the brown fat disappears during the early childhood. In adults another members of the UCP family can be found - UCP2 and UCP3. It is widely accepted that these proteins affect lipid metabolism and energy expenditure. They are intensively studied owing to their possible use in the therapy of obesity. However, their physiological function has not been yet fully established.
Thermogenic uncoupling has been proven only for UCP1 in brown adipose tissue. All other isoforms of UCPs are potentially acting in suppression of mitochondrial reactive oxygen species (ROS) production. In this contribution we show that BAT mitochondria can be uncoupled by lauric acid in the range of approximately 100 nM when endogenous fatty acids are combusted by carnitine cycle and beta-oxidation is properly separated from the uncoupling effect. Respiration increased up to 3 times when related to the lowest fatty acid content (BSA present plus carnitine cycle). We also illustrated that any effect leading to more coupled states leads to enhanced H2O2 generation and any effect resulting in uncoupling gives reduced H2O2 generation in BAT mitochondria. Finally, we report doubling of plant UCP transcript in cells as well as amount of protein detected by 3H-GTP-binding sites in mitochondria of shoots and roots of maize seedlings subjected to the salt stress.
- MeSH
- Cell Respiration MeSH
- Financing, Organized MeSH
- Guanosine Triphosphate metabolism MeSH
- Adipose Tissue, Brown metabolism MeSH
- Ion Channels MeSH
- Carnitine metabolism MeSH
- Plant Roots metabolism MeSH
- Zea mays metabolism MeSH
- Lauric Acids pharmacology metabolism MeSH
- Fatty Acids metabolism MeSH
- Membrane Proteins physiology MeSH
- Mitochondrial Proteins MeSH
- Mitochondria metabolism MeSH
- Oxidative Stress MeSH
- Hydrogen Peroxide metabolism MeSH
- Reactive Oxygen Species metabolism MeSH
- Plant Proteins physiology MeSH
- Uncoupling Agents pharmacology metabolism MeSH
- Mammals MeSH
- In Vitro Techniques MeSH
- Carrier Proteins physiology MeSH
- Binding Sites MeSH
- Plant Shoots metabolism MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Review MeSH
International journal of obesity and related metabolic disorders, ISSN 0307-0565 vol. 23, suppl. 6, June 1999
S74 s. ; 30 cm
- MeSH
- Membrane Proteins MeSH
- Mitochondria MeSH
- Obesity MeSH
- Reducing Agents MeSH
- Carrier Proteins MeSH
- Publication type
- Congress MeSH
- Conspectus
- Fyziologie člověka a srovnávací fyziologie
- NML Fields
- vnitřní lékařství
- biochemie
Odpřahující protein 2 (UCP2, uncoupling protein 2) objevený v roce 1997 je homologem rozpřahujícího proteinu 1 (UCP1), který byl objeven v mitochondriích hnědé tukové tkáně novorozených savců a dospělých hibernantů jako součást mechanismu netřesové termogeneze. Zatímco UCP1 byl prokázán pouze v hnědé tukové tkáni, UCP2 je exprimován v kosterním svalu, bílé tukové tkáni, plicích a v dalších buněčných populacích. Odpřahující proteiny fungují jako iontové kanály. Jejich otevření snižuje mitochondriální membránový potenciál, tím se snižuje účinnost energetické přeměny – snižuje se tvorba ATP a zvyšuje se uvolnění energie ve formě tepla. UCP proteiny tím, že odpřahují procesy oxidace od tvorby ATP, zvyšují oxidaci substrátů, snižují podíl redukovaných komponent respiračního řetězce a tím redukují produkci reaktivních kyslíkových radikálů mitochondriemi. V tomto článku jsou popsány možné funkce UCP2.
Uncoupling protein 2 (UCP2), discovered in 1997, is the fi rst homologue of uncoupling protein 1 (UCP1) that was discovered in mitochondria of brown adipose tissue of newborn mammals and adult hibernators as the part of mechanism in non-shivering thermogenesis. While UCP1 was presented only in brown adipose tissue, UCP2 is expressed in skeletal muscle, white adipose tissue, lungs and in other cell populations. Uncoupling proteins work as ion channels. Opening of these channels decrease the mitochondrial membrane potential thereby the effi ciency of energy conversion is decreased – it is decreased production of ATP and is increased dissipation of energy in the form of heat. Uncoupling proteins uncouple the process of oxidation from the ATP formation, increase the substrate oxidation and decrease the part of reduced components of respiratory chain thereby reducing the production of reactive oxygen species in mitochondria. In this review possible functions of UCP2 are also described.
- MeSH
- Adenosine Triphosphatases metabolism MeSH
- Financing, Organized MeSH
- Adipose Tissue, Brown metabolism MeSH
- Insulin secretion MeSH
- Mitochondrial Proteins metabolism MeSH
- Disease Models, Animal MeSH
- Cell Transformation, Neoplastic metabolism MeSH
- Obesity metabolism MeSH
- Oxidative Stress MeSH
- Oxidative Phosphorylation MeSH
SIGNIFICANCE: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δp or its potential component, ΔΨ, which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1-5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δp dissipation decreases superoxide formation dependent on Δp. UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. CRITICAL ISSUES: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg2+, or increased pyruvate accumulation may initiate UCP-mediated redox signaling. FUTURE DIRECTIONS: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667-714.
Uncoupling protein-2, discovered in 1997, is the first described homologue of uncoupling protein-1. Uncoupling proteins increase the permeability of inner mitochondrial membrane for protons, decrease the efficiency of energy conversion, inhibit the ATP synthesis and stimulate energy release in form of heat. Uncoupling proteins also increase the substrate oxidation and reduce production of reactive oxygen species in mitochondria. The present study was conducted to assess the effects of acute treatment with triiodothyronine on uncoupling protein-2 mRNA levels in Wistar rats. Intraperitoneal injection of one dose of triiodothyronine (200 μg/kg rat body weight) increased mRNA expression of uncoupling protein-2 in liver tissue almost 2-fold after 12 h. Concentrations of total triiodothyronine and free triiodothyronine in serum were increased 122-fold and 76-fold, respectively. These results suggest that gene coding uncoupling protein-2 is gene inducible in the liver shortly after single administration of T3. Data about the kinetics of T3 mediated induction of UCP-2 mRNA during the first 24 h after treatment were not available in literature so far and therefore constitute our priority findings.
- MeSH
- Energy Metabolism MeSH
- Gene Expression MeSH
- Glycerolphosphate Dehydrogenase MeSH
- Mitochondria, Liver * enzymology genetics metabolism MeSH
- Liver enzymology metabolism drug effects MeSH
- RNA, Messenger isolation & purification MeSH
- Rats, Wistar MeSH
- Reactive Oxygen Species MeSH
- Triiodothyronine * pharmacokinetics pharmacology blood therapeutic use MeSH
- Uncoupling Protein 2 * drug effects MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
Molecular dynamics (MD) simulations of uncoupling proteins (UCP), a class of transmembrane proteins relevant for proton transport across inner mitochondrial membranes, represent a complicated task due to the lack of available structural data. In this work, we use a combination of homology modelling and subsequent microsecond molecular dynamics simulations of UCP2 in the DOPC phospholipid bilayer, starting from the structure of the mitochondrial ATP/ADP carrier (ANT) as a template. We show that this protocol leads to a structure that is impermeable to water, in contrast to MD simulations of UCP2 structures based on the experimental NMR structure. We also show that ATP binding in the UCP2 cavity is tight in the homology modelled structure of UCP2 in agreement with experimental observations. Finally, we corroborate our results with conductance measurements in model membranes, which further suggest that the UCP2 structure modeled from ANT protein possesses additional key functional elements, such as a fatty acid-binding site at the R60 region of the protein, directly related to the proton transport mechanism across inner mitochondrial membranes.
- MeSH
- Adenosine Triphosphate chemistry metabolism MeSH
- Ion Transport MeSH
- Protein Conformation * MeSH
- Fatty Acids chemistry metabolism MeSH
- Membrane Proteins chemistry MeSH
- Mitochondrial Proteins chemistry metabolism MeSH
- Mice MeSH
- Amino Acid Sequence MeSH
- Molecular Dynamics Simulation * MeSH
- Protein Stability MeSH
- Uncoupling Protein 2 chemistry metabolism MeSH
- Protein Binding MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Research on brown adipose tissue and its hallmark protein, mitochondrial uncoupling protein UCP1, has been conducted for half a century and has been traditionally studied in the Institute of Physiology (AS CR, Prague), likewise UCP2 residing in multiple tissues for the last two decades. Our group has significantly contributed to the elucidation of UCP uncoupling mechanism, fully dependent on free fatty acids (FFAs) within the inner mitochondrial membrane. Now we review UCP2 physiological roles emphasizing its roles in pancreatic beta-cells, such as antioxidant role, possible tuning of redox homeostasis (consequently UCP2 participation in redox regulations), and fine regulation of glucose-stimulated insulin secretion (GSIS). For example, NADPH has been firmly established as being a modulator of GSIS and since UCP2 may influence redox homeostasis, it likely affects NADPH levels. We also point out the role of phospholipase iPLA2 isoform gamma in providing FFAs for the UCP2 antioxidant function. Such initiation of mild uncoupling hypothetically precedes lipotoxicity in pancreatic beta-cells until it reaches the pathological threshold, after which the antioxidant role of UCP2 can be no more cell-protective, for example due to oxidative stress-accumulated mutations in mtDNA. These mechanisms, together with impaired autocrine insulin function belong to important causes of Type 2 diabetes etiology.
- MeSH
- Antioxidants metabolism MeSH
- Insulin-Secreting Cells metabolism MeSH
- Glucose metabolism MeSH
- Insulin biosynthesis MeSH
- Ion Channels metabolism MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Mitochondrial Proteins metabolism MeSH
- Mitochondria metabolism MeSH
- Oxidation-Reduction MeSH
- Oxidative Stress physiology MeSH
- Reactive Oxygen Species metabolism MeSH
- Gene Expression Regulation physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
