UNCOUPLE ……………………… …6 II. Uncoupling protein 2 (UCP

    UNCOUPLEELECTRON TRANSPORT AND                HEATGENERATION SUBMITTEDTO:Dr. M. TARIQ ZAHID                    SUBMITTED BY: NIMRA SHOUKAT            ROLLNO: 2030-BH-Z-14SUBJECT: GENERAL BIOCHEMISTRY CONTENTS1.

    Introduction…………………………………………………………32.    Uncouple electron transport…………………………………………43.    Uncoupling proteins……………………………………………….

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..44.    Types of uncouplingproteins……………………………………….

5                              I.           Uncoupling protein 1(UCP 1)…… ……………………… …6                           II.

           Uncoupling protein 2 (UCP 2)……………………………….6                        III.           Uncoupling protein 3 (UCP 3)………………… ……………6                       IV.           Uncoupling protein 4 (UCP 4)…………… …………………7                          V.           Uncoupling protein 5 (UCP 5)………………..

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75.    Heat generation by uncouple electrontransport…………………….76.    Protein- independent uncoupling………………………………….

..107.    Conclusion…………………………………………………………..118.    References………………………………………………………….

.12   UNCOUPLEELECTRON TRANSPORT AND HEAT GENERATION INTRODUCTION:Mitochondria is presentin the cytoplasm of cells of all eukaryotic organisms. This organelle isessential for the cell function and survival. The basic function ofmitochondria is to convert the latent energy of nutrients into the storedenergy (ATP).

The organic nutrients are obtained from food molecules such asfats, proteinsand carbohydrates. Different metabolic intermediates such as fatty acids, aminoacids and simple sugars are formed through the hydrolysation of thesemacromolecules by various enzymes. These intermediates are then subjected to oxidationin the mitochondria alongwith creating a proton gradient in a process called oxidative phosphorylation. In electron transport chain, electronsfrom energy-rich molecules such as fatty acids and glucose are transported tothe inner mitochondrial membrane, which contains specific proteins that can acceptand donate the electrons to next electron acceptor in the chain. In the mitochondria, thetwo processes i-e proton pumping and electron transport are coupled. This producesan electrochemical gradient called protonmotive force.

The proton gradient generates potential energy which is usedto drive the phosphorylation of ADP to ATP through ATP synthase by usingfollowing two gradients:·         Themembrane potential creates an electrical gradient.·        The pH difference creates a very smallchemical gradient.    UNCOUPLEELECTRON TRANSPORT:The experimental observations with isolatedmitochondria led to the empiricalderivation of    conceptof uncoupling of ATP synthesis and electron transport chain. This is aspecialized process in which protons move back into the matrix of mitochondriawithout passing through ATP synthase and dissipate the existing electrochemicalgradient across mitochondrial membrane without generating ATP. This phenomenonis known as Uncoupling of OxidativePhosphorylation.

It is basically the delinking of electron transport andATP production. This uncoupling occurs naturally due to specialized uncouplingproteins in the cell which dissipate the protein motive force and providepassage for backflow of protons. Since the protons move back to matrix withoutentering ATP synthase, the amount of energy obtained from the oxidation of the substratesis actually wasted and liberated as heat. The cell attempts to maintain electrochemicalgradient through proton pumping and electron transfer and results in·        Heat production·        Increased oxygen consumption     UNCOUPLINGPROTEINS:   Theuncoupling proteins are a group of mitochondrial negatively charged proteinswhich are situated on the inner membrane of mitochondria. They form channelsthrough the inner mitochondrial membrane that can conduct protons fromintermembrane space to matrix, thereby short-circuiting ATP synthase.

Thisfamily of uncoupling proteins shares many functional and structuralcharacteristics. All these proteins contain tripartite structure with 3 repeatsof about 100 amino acids, each having 2 hydrophobic stretches which link totransmembrane ?-helices. So, Uncoupling proteinshave 6 ?-helical regions which extend lipid bilayer. The basic unit of uncouplingproteins is a dimer made up of   twosubunits (identical) containing twelve transmembrane helices.Asthe uncoupling proteins affect the metabolic efficiency, so the difference intheir levels may contribute to the tendency towards obesity in some individualsor populations. UCPs may also lessen the amount of reduced CoQ available toform oxygen free radicals, so reducing the mitochondrial and cell injury.

Theymay also have some association with insulin resistance.    TYPESOF UNCOUPLING PROTEINS:Thereare five types of uncoupling proteins in mammals1)      Uncouplingprotein 1 (UCP1)2)      Uncouplingprotein 2 (UCP2)3)      Uncouplingprotein 3 (UCP3)4)      Uncouplingprotein 4 (UCP4)5)      Uncouplingprotein 5 (UCP5)   UNCOUPLING PROTEIN 1(UCP1):Uncouplingprotein1 is also called thermogenin.It is present particularly in inner membrane of mitochondria in the brownadipose tissues and its basic function is to catalyze the non-shivering thermogenesis.

UCP1 is triggered by fatty acids and it works synergistically with thyroidhormones and norepinephrine. UNCOUPLING PROTEIN 2(UCP2):Uncouplingprotein 2 is found ubiquitously in all human tissues. It has following functions:·        plays a regulative role in insulin release·        role in immunity·        provides neuroprotection against oxidativestress ·        regulates pain and ethanol sensitivity      UNCOUPLING PROTEIN 3(UCP3):Uncouplingprotein 3 is mainly present in the skeletal muscles. However, it is alsoexpressed in the heart tissue and brown adipose tissues. UCP3 was discovered inearly 1997.

 The major functions of UCP 3are control of adaptive thermogenesis, reactive oxygen species control, controlof the cellular energy balance, prevention of oxidative stress, the regulationof fatty acid oxidation and adenosine-5′-triphosphate synthesis. It also playsrole in prevention of obesity, insulin resistance and T2DM.  UNCOUPLING PROTEIN 4(UCP4):Uncouplingprotein 4 is present in many brain tissues.

Its level is low in the spinal cord,substantia nigra and corpus callosum. Uncoupling protein 4 modulates neuronalenergy metabolism, rises glucose uptake and glycolytic pathway of adenosine-5′-triphosphateformation. Moreover, it regulates Ca2+ homeostasis and influences the influx ofCa2+ into the endoplasmic reticulum. The overexpression of uncoupling protein 4in SH-SY5Y cells raises adenosine-5′-triphosphate levels linked with increasedrespiratory rate.UNCOUPLING PROTEIN 5(UCP5):Uncoupling protein 5 was first described andnamed as brain mitochondrial carrierprotein-1 (BMCP1). Uncoupling protein 5 has similar characteristics to UCP 4,but differs in enhancing mitochondrial properties. The overexpression ofuncoupling protein 5 preserves adenosine-5′-triphosphate levels, maintains oxidativephosphorylation and attenuates reactive oxygen species production.

HEAT GENERATION BY UNCOUPLE ELECTRON TRANSPORT:In1960, it was proposed that endothermic animals utilize the process of uncoupledoxidative phosphorylation to generate heat in the condition of critically lowambient temperature. In mammals, uncoupled oxidative phosphorylation serves thepurpose of non-shivering thermogenesis in brown adipose tissues. The brown colour of this tissue actually arises due tothe large number of mitochondria. Brown adipose tissue has special significancein the animals which need to produce heat e.g hibernating mammals. Inhibernation, temperature of body falls and the metabolism slows down forpreservation of fuel stores. The brown adipose tissues produce heat whichfacilitates the awakening from hibernation. The adult mammals for examplehumans usually do not have any problem in producing heat because ratio of the body mass to body surface area is in the favour of producing large amount of heat.

Instead of it, the adulthumans lose heat through various ways for example sweating and by dilating theblood vessels in skin. So, the adult humans have very little proportionof brown adipose tissues but in infants,ratio of the body mass to body surface area is different and theyneed a mechanism for heat generation. So, the brownadipose tissue is of clear significance in infants. The infants have brown fatdeposits along breastplate, neck, between scapulae and around kidneys toprotect them from cold. However, it is lost during development.                                          Brown Fat Cell                              Microscopicview of Bown adipose tissue  Brown adipose tissues possess a very unique metabolicfeature.

This tissue can oxidize substrates through Krebs cycle in mitochondria;unlike in any other tissue this process can be uncoupled from the production ofATP when this tissue is triggered by sympathetic nervous system.  In the mitochondria of brown adiposetissues, a specialized uncoupling protein (thermogenin) uncouples this process,thus allowing proton gradient across the inner membrane ofmitochondria to be short-circuited or dissolute. UCP is associated to theother proteins which transport the substrates across the inner membrane of mitochondriabut it has become specialized as a proton channel. The discharge of protongradient leads to the liberation of heatfrom the oxidation of the substrates, without trapping free energy in thehigh-energy compounds. Inresponse to cold, sympathetic nerve endings release norepinephrine whichactivates a lipase in brown adipose tissues that release fatty acids fromtriglycerides. Fatty acids are the weak  acidswhich can cross membrane in their both deprotonated and protonated forms. The effectsof the fatty acids are interconnected to:Ø increasing uncoupling Ø increasing reactive oxygen speciesgenerationØ opening of mitochondrial permeabilitytransition poresØ  modulatingthe effects of sex steroid hormone and thyroid hormones. Fattyacids act as a fuel for tissue i-e oxidized to produce the electrochemicalpotential gradient and ATP and participate directly in proton conductancechannel by activating UCP1 along with reduced CoQ.

When UCP1 is triggered bypurine nucleotides, fatty acids and CoQ, it transports protons from cytosolicside of the inner membrane of mitochondria back into mitochondrial matrixwithout ATP generation. Thus, it leads to partial uncoupling of phosphorylationand generates additional heat.        PROTEIN INDEPENDENT UNCOUPLING: Apart from uncoupling proteins, certain chemical uncoupling agents can break the connection between electron transport and ATP synthesis.

These uncoupling agents are also known as proton ionophores. This protein-independent uncoupling mechanism directly enhances permeability of the lipid bilayer of inner membrane of mitochondria to H+. One very significant class of the compounds which uncouple mitochondria by this process is represented by the weak lipid-soluble acids. These chemical uncouplers, mostly aromatic compounds, enhance the H+ permeability of  lipid bilayer by enabling H+ transport across hydrophobic barrier. These uncouplers dissipate the gradient due to two factors: ·         Hydrophobicity ·         Delocalization of negative charge   The mechanism of action of chemical uncouplers is well established. The energized mitochondria build up  ?? and ?pH across inner mitochondrial membrane to make matrix  more alkaline and negatively charged as compared to external medium. The weak lipophilic acids in their protonated form (A-H+) get dissolved in the inner membrane and diffuse through lipid phase into mitochondrial matrix and dissociate into the acid anion (A-) and H+ and in this way, dissipate the ?pH.

However, they can’t accrue in matrix because their anion is also soluble in lipid phase due to charge delocalization over  aromatic ring. The acid anion is then expelled from the mitochondria downgradient of ?? (more positive outside) and dissipate the ??. This futileproton-shuttling cycle is further repeated to the point when there is no more?? or ?pH across inner membrane of mitochondria. Several medicines candissipate the electrochemical gradient by this mechanism.    Someexamples of chemical uncouplers of oxidative phosphorylation are following:·        2,4-Dinitrophenol (DNP)·        Dinitrocresol·        Pentachlorophenol·        Carbonylcyanidep-trifluoromethoxyphenylhydrazone (FCCP)·        Chloro carbonyl cyanide phenyl hydrazone(CCCP)Amongall of these chemical uncoupling agents, carbonylcyanide p-trifluoromethoxyphenylhydrazone(FCCP) and 2,4-Dinitrophenol (DNP) are the most common.

   CONCLUSION:Theuncoupling of oxidative phosphorylation and electron transport by eitheruncoupling proteins or chemical uncoupling agents results in generation ofadditional heat due to proton leak back into the mitochondrial matrix. REFERENCES ·       Hroudova, J., & Fisar, Z. (2013). Control mechanisms in mitochondrial oxidativephosphorylation. Neural RegenerationResearch, 8 (4), 363-375.

·       Andrews, Z. B., Diano. S, & Horvarth,T. L.

(2005). Mitochondrial uncoupling proteins in the CNS: in support offunction and survival. Nature ReviewsNeuroscience, 6 (11), 829-840.·       Busiello, R. A, Savarese, S.

, , A. (2015). Mitochondrial uncoupling proteins and energymetabolism.  frontiers in Physiology, 6 (36), 1-7.

·       Lieberman, M., Marks, A. D, & Smith,C. (2006).

  Mark’s Essentials of MedicalBiochemistry, A Clinical Approach, 1ST Edition. Lippincott Williams& Wilkins, USA.·       http://www.oxphos.org/index.php?option=com_content&task=view&id=39&Itemid=75·       https://www.alpfmedical.info/adipose-tissue/brown-adipose-tissue-and-the-concept-of-uncoupling.html