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

 

 

 

UNCOUPLE
ELECTRON TRANSPORT AND                HEAT
GENERATION

 

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SUBJECT: GENERAL BIOCHEMISTRY

 

CONTENTS

1.    
Introduction…………………………………………………………3

2.    
Uncouple electron transport…………………………………………4

3.    
Uncoupling proteins…………………………………………………4

4.    
Types of uncoupling
proteins……………………………………….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)………………..………………7

5.    
Heat generation by uncouple electron
transport…………………….7

6.    
Protein- independent uncoupling……………………………………10

7.    
Conclusion…………………………………………………………..11

8.    
References…………………………………………………………..12

 

 

 

UNCOUPLE
ELECTRON TRANSPORT AND HEAT GENERATION

 

INTRODUCTION:

Mitochondria is present
in the cytoplasm of cells of all eukaryotic organisms. This organelle is
essential for the cell function and survival. The basic function of
mitochondria is to convert the latent energy of nutrients into the stored
energy (ATP). The organic nutrients are obtained from food molecules such as
fats, proteins
and carbohydrates. Different metabolic intermediates such as fatty acids, amino
acids and simple sugars are formed through the hydrolysation of these
macromolecules by various enzymes. These intermediates are then subjected to oxidation
in the mitochondria alongwith creating a proton gradient in a process called oxidative phosphorylation. In electron transport chain, electrons
from energy-rich molecules such as fatty acids and glucose are transported to
the inner mitochondrial membrane, which contains specific proteins that can accept
and donate the electrons to next electron acceptor in the chain.

In the mitochondria, the
two processes i-e proton pumping and electron transport are coupled. This produces
an electrochemical gradient called proton
motive force. The proton gradient generates potential energy which is used
to drive the phosphorylation of ADP to ATP through ATP synthase by using
following two gradients:

·        
 The
membrane potential creates an electrical gradient.

·        
The pH difference creates a very small
chemical gradient.

 

 

UNCOUPLE
ELECTRON TRANSPORT:

The experimental observations with isolated
mitochondria led to the empirical
derivation of    concept
of uncoupling of ATP synthesis and electron transport chain. This is a
specialized process in which protons move back into the matrix of mitochondria
without passing through ATP synthase and dissipate the existing electrochemical
gradient across mitochondrial membrane without generating ATP. This phenomenon
is known as Uncoupling of Oxidative
Phosphorylation. It is basically the delinking of electron transport and
ATP production. This uncoupling occurs naturally due to specialized uncoupling
proteins in the cell which dissipate the protein motive force and provide
passage for backflow of protons. Since the protons move back to matrix without
entering ATP synthase, the amount of energy obtained from the oxidation of the substrates
is actually wasted and liberated as heat. The cell attempts to maintain electrochemical
gradient through proton pumping and electron transfer and results in

·        
Heat production

·        
Increased oxygen consumption

 

 

 

 

UNCOUPLING
PROTEINS:

 

The
uncoupling proteins are a group of mitochondrial negatively charged proteins
which are situated on the inner membrane of mitochondria. They form channels
through the inner mitochondrial membrane that can conduct protons from
intermembrane space to matrix, thereby short-circuiting ATP synthase. This
family of uncoupling proteins shares many functional and structural
characteristics. All these proteins contain tripartite structure with 3 repeats
of about 100 amino acids, each having 2 hydrophobic stretches which link to
transmembrane ?-helices. So, Uncoupling proteins
have 6 ?-helical regions which extend lipid bilayer. The basic unit of uncoupling
proteins is a dimer made up of   two
subunits (identical) containing twelve transmembrane helices.

As
the uncoupling proteins affect the metabolic efficiency, so the difference in
their levels may contribute to the tendency towards obesity in some individuals
or populations. UCPs may also lessen the amount of reduced CoQ available to
form oxygen free radicals, so reducing the mitochondrial and cell injury. They
may also have some association with insulin resistance.

 

 

 

TYPES
OF UNCOUPLING PROTEINS:

There
are five types of uncoupling proteins in mammals

1)      Uncoupling
protein 1 (UCP1)

2)      Uncoupling
protein 2 (UCP2)

3)      Uncoupling
protein 3 (UCP3)

4)      Uncoupling
protein 4 (UCP4)

5)      Uncoupling
protein 5 (UCP5)

 

 

UNCOUPLING PROTEIN 1
(UCP1):

Uncoupling
protein1 is also called thermogenin.
It is present particularly in inner membrane of mitochondria in the brown
adipose tissues and its basic function is to catalyze the non-shivering thermogenesis.
UCP1 is triggered by fatty acids and it works synergistically with thyroid
hormones and norepinephrine.

 

UNCOUPLING PROTEIN 2
(UCP2):

Uncoupling
protein 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 oxidative
stress

·        
regulates pain and ethanol sensitivity

 

 

 

 

 

UNCOUPLING PROTEIN 3
(UCP3):

Uncoupling
protein 3 is mainly present in the skeletal muscles. However, it is also
expressed in the heart tissue and brown adipose tissues. UCP3 was discovered in
early 1997.  The major functions of UCP 3
are control of adaptive thermogenesis, reactive oxygen species control, control
of the cellular energy balance, prevention of oxidative stress, the regulation
of fatty acid oxidation and adenosine-5′-triphosphate synthesis. It also plays
role in prevention of obesity, insulin resistance and T2DM.

 

UNCOUPLING PROTEIN 4
(UCP4):

Uncoupling
protein 4 is present in many brain tissues. Its level is low in the spinal cord,
substantia nigra and corpus callosum. Uncoupling protein 4 modulates neuronal
energy metabolism, rises glucose uptake and glycolytic pathway of adenosine-5′-triphosphate
formation. Moreover, it regulates Ca2+ homeostasis and influences the influx of
Ca2+ into the endoplasmic reticulum. The overexpression of uncoupling protein 4
in SH-SY5Y cells raises adenosine-5′-triphosphate levels linked with increased
respiratory rate.

UNCOUPLING PROTEIN 5
(UCP5):

Uncoupling protein 5 was first described and
named as brain mitochondrial carrier
protein-1 (BMCP1). Uncoupling protein 5 has similar characteristics to UCP 4,
but differs in enhancing mitochondrial properties. The overexpression of
uncoupling protein 5 preserves adenosine-5′-triphosphate levels, maintains oxidative
phosphorylation and attenuates reactive oxygen species production.

HEAT GENERATION BY UNCOUPLE ELECTRON TRANSPORT:

In
1960, it was proposed that endothermic animals utilize the process of uncoupled
oxidative phosphorylation to generate heat in the condition of critically low
ambient temperature. In mammals, uncoupled oxidative phosphorylation serves the
purpose of non-shivering thermogenesis in brown adipose tissues. The brown colour of this tissue actually arises due to
the large number of mitochondria. Brown adipose tissue has special significance
in the animals which need to produce heat e.g hibernating mammals. In
hibernation, temperature of body falls and the metabolism slows down for
preservation of fuel stores. The brown adipose tissues produce heat which
facilitates the awakening from hibernation. The adult mammals for example
humans 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 adult
humans lose heat through various ways for example sweating and by dilating the
blood vessels in skin. So, the adult humans have very little proportion
of brown adipose tissues but in infants,
ratio of the body mass to body surface area is different and they
need a mechanism for heat generation. So, the brown
adipose tissue is of clear significance in infants. The infants have brown fat
deposits along breastplate, neck, between scapulae and around kidneys to
protect them from cold. However, it is lost during development.

 

 

          

    

 

                       Brown Fat Cell                              Microscopic
view of Bown adipose tissue

 

 

Brown adipose tissues possess a very unique metabolic
feature. This tissue can oxidize substrates through Krebs cycle in mitochondria;
unlike in any other tissue this process can be uncoupled from the production of
ATP when this tissue is triggered by sympathetic nervous system.  In the mitochondria of brown adipose
tissues, a specialized uncoupling protein (thermogenin) uncouples this process,
thus allowing proton gradient across the inner membrane of
mitochondria to be short-circuited or dissolute. UCP is associated to the
other proteins which transport the substrates across the inner membrane of mitochondria
but it has become specialized as a proton channel. The discharge of proton
gradient leads to the liberation of heat
from the oxidation of the substrates, without trapping free energy in the
high-energy compounds.

In
response to cold, sympathetic nerve endings release norepinephrine which
activates a lipase in brown adipose tissues that release fatty acids from
triglycerides. Fatty acids are the weak

 

acids
which can cross membrane in their both deprotonated and protonated forms. The effects
of the fatty acids are interconnected to:

Ø 
increasing uncoupling

Ø 
increasing reactive oxygen species
generation

Ø 
opening of mitochondrial permeability
transition pores

Ø  modulating
the effects of sex steroid hormone and thyroid hormones.

Fatty
acids act as a fuel for tissue i-e oxidized to produce the electrochemical
potential gradient and ATP and participate directly in proton conductance
channel by activating UCP1 along with reduced CoQ. When UCP1 is triggered by
purine nucleotides, fatty acids and CoQ, it transports protons from cytosolic
side of the inner membrane of mitochondria back into mitochondrial matrix
without ATP generation. Thus, it leads to partial uncoupling of phosphorylation
and 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 down
gradient of ?? (more positive outside) and dissipate the ??. This futile
proton-shuttling cycle is further repeated to the point when there is no more
?? or ?pH across inner membrane of mitochondria. Several medicines can
dissipate the electrochemical gradient by this mechanism.

 

 

 

Some
examples of chemical uncouplers of oxidative phosphorylation are following:

·        
2,4-Dinitrophenol (DNP)

·        
Dinitrocresol

·        
Pentachlorophenol

·        
Carbonylcyanide
p-trifluoromethoxyphenylhydrazone (FCCP)

·        
Chloro carbonyl cyanide phenyl hydrazone
(CCCP)

Among
all of these chemical uncoupling agents, carbonylcyanide p-trifluoromethoxyphenylhydrazone
(FCCP) and 2,4-Dinitrophenol (DNP) are the most common.

 

 

CONCLUSION:

The
uncoupling of oxidative phosphorylation and electron transport by either
uncoupling proteins or chemical uncoupling agents results in generation of
additional heat due to proton leak back into the mitochondrial matrix.

 

REFERENCES

 

·       
Hroudova, J., & Fisar, Z. (2013). Control mechanisms in mitochondrial oxidative
phosphorylation. Neural Regeneration
Research, 8 (4), 363-375.

·       
Andrews, Z. B., Diano. S, & Horvarth,
T. L. (2005). Mitochondrial uncoupling proteins in the CNS: in support of
function and survival. Nature Reviews
Neuroscience, 6 (11), 829-840.

·       
Busiello, R. A, Savarese, S., &
Lombardi, A. (2015). Mitochondrial uncoupling proteins and energy
metabolism.  frontiers in Physiology, 6 (36), 1-7.

·       
Lieberman, M., Marks, A. D, & Smith,
C. (2006).  Mark’s Essentials of Medical
Biochemistry, 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