Thermogenin, uncoupling protein

Thermogenin is an uncoupling protein present in the plasma membrane of prokaryotes and inner membrane of mitochondria of plants and animal cells. Uncoupling protein involved in the transport of ions and thermogenesis. Thermogenin protein can dissipate the proton gradient that was generated by NADH-powered pumping. The three well-known uncoupling proteins including UCP1, UCP2, and UCP3.



Uncoupling protein-1 (UCP1) is found on mitochondrial membrane of brown adipose tissue (BAT) and that contribute to generate heat by non-shivering thermogenesis, hence the protein termed thermogenin. This uncoupler plays a positive role in newborn babies with generating body heat due to their high surface area-volume ratio.

Uncoupling protein is a transmembrane protein of inner mitochondrial membrane that disturbs the proton gradient by increasing the permeability of protons through the inner mitochondrial membrane from intermembrane space to the mitochondrial matrix during oxidative phosphorylation.

The mechanism of uncoupling protein is closely related to other mitochondrial inner membrane proton channels, adenine nucleotide translocator (mitochondrial metabolite transporters) that allows the transport of protons into the mitochondrial matrix from mitochondrial intermembrane space.


Key points:

  1. Uncoupling protein can be activated by fatty acids and inhibited by purine nucleotides (ADP and GDP).
  2. The function of uncoupling protein (thermogenin) is similar to the function of adenine nucleotide translocator (inner membrane proton channels).
  3. UCP1 found only in brown adipose tissue.
  4. UCP1 is the only protein that can able to generate heat as a non-shivering way by considering body metabolic condition.
  5. sympathetic neurotransmitter norepinephrine stimulates the activity of UCP1 through signaling cascade.


Mechanism of thermogenin

Fatty acids in the brown adipose tissue activate the uncoupling protein-1, while nucleotides inhibit the function of the transporter. The activation process by fatty acids occur in following signaling cascade.

Tterminals of neurons in the Sympathetic nervous system release the neurotransmitter, Norepinephrine (catecholamine hormone), in turn, that actives the Beta-3 adrenergic receptor present on the plasma membrane. The triggered receptor activates adenylyl cyclase enzyme. This enzyme, in turn, catalyzes the synthesis of second messenger, cyclic AMP (cAMP) from ATP molecules. Then, produced cAMP activates the protein kinase A by releasing catalytic subunits (C subunits) from its regulatory R subunits. The released C subunits of protein kinase A activate the triacylglycerol lipase by phosphorylation, thus the activated lipase cleaves the bulk molecule triacylglycerols into free fatty acids. The released fatty acids activate the uncoupling protein-1.

During the termination of thermogenesis, the function of uncoupling protein can be inhibited by purine nucleotides (GDP and ADP), thus thermogenin is inactivated and remaining fatty acids are disposed off through oxidation, that facilitates the cell to return its normal energy-conserving state.


Function of uncoupling protein

  1. Involved in the sending of protons-return back from the mitochondrial intermembrane space to the mitochondrial matrix.
  2. Reduces the rate of ATP synthesis by disturbing the proton motive force, which is a need for oxidative phosphorylation.
  3. Involved in the generation of heat in the brown adipose tissue of new born babies.
  4. Promotes the rate of oxidation of fats.
  5. Involved in the regulation of free radicals and reactive oxygen species (ROS).
  6. Increases the oxidation of NADH molecule to generate an electrochemical gradient across mitochondrial membrane.


Scientific focus on uncoupling protein

Gene transfer therapy is the current scientific target to deliver the gene into target place of the DNA, that encodes uncoupling protein. In other way, experiments on modulation of thermogenin to enhance its expression in significant amount in order to increase the metabolic rate in fat contained-persons, thus treatment with gene modulation may reduce the obesity problems.


Which uncoupling protein is a major contributor to generate heat in brown adipose tissue?

In the journal of Biochim Biophys Acta, Nedergaard et al., 2001 stated that our expression analysis on uncoupling proteins revealed that UCP1 has uniqueness for generating the heat in brown adipose tissue compared to other uncoupling proteins UCP2 and UCP3. In their studies they found the higher expression of UCP1 gene during cold acclimation (in adults or perinatally) and overfeeding, and reduced expression during fasting and in the patients with genetic obesity.

Finally, their study concluded that UCP1 is unique uncoupling protein from others (UCP2 and UCP3) and is the only protein that can mediate adaptive non-shivering thermogenesis and ensuing metabolic inefficiency.



Data source:

Palou A, Picó C, Bonet ML, Oliver P.The uncoupling protein, thermogenin. Int J Biochem Cell Biol. 1998 Jan;30(1):7-11.

Mortola JP, Naso L.Brown adipose tissue and its uncoupling protein in chronically hypoxic rats.Clin Sci (Lond). 1997 Oct;93(4):349-54.

Nedergaard J, Golozoubova V, Matthias A, Asadi A, Jacobsson A, Cannon B. UCP1: the only protein able to mediate adaptive non-shivering thermogenesis and metabolic inefficiency.Biochim Biophys Acta. 2001 Mar 1;1504(1):82-106.

Golozoubova V, Hohtola E, Matthias A, Jacobsson A, Cannon B, Nedergaard J. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold.

Nedergaard J, Golozoubova V, Matthias A, Shabalina I, Ohba K, Ohlson K, Jacobsson A, Cannon B. Life without UCP1: mitochondrial, cellular and organismal characteristics of the UCP1-ablated mice. Biochem Soc Trans. 2001 Nov;29(Pt 6):756-63.

Matthias A, Ohlson KB, Fredriksson JM, Jacobsson A, Nedergaard J, Cannon B. Thermogenic responses in brown fat cells are fully UCP1-dependent. UCP2 or UCP3 do not substitute for UCP1 in adrenergically or fatty acid-induced thermogenesis.J Biol Chem. 2000 Aug 18;275(33):25073-81.








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