Uncoupling protein 1

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Uncoupling protein 1

Description

Uncoupling protein 1 (UCP1) is also called thermogenin and is predominantly found in brown adipose tissue (BAT). UCP1 belongs to the gene family of uncoupling proteins. It is vital for the maintenance of body temperature, especially for small mammals. As the essential component of non-shivering thermogenesis, it possesses the ability to build and open a pore in the inner mitochondrial membrane through which protons may flow along their electrochemical gradient, generated by respiration, bypassing the ATP-producing re-entry site at the F1F0-ATP synthase. Thereby the energy stored in the electrochemical gradient is dissipated as heat.

Abbreviation: UCP1

Communicated by Bufe A 2017-05-04.
UCP1[1] can be inhibited by cytosolic purine nucleotides in their di- and tri-phosphate form such as ADP, ATP, GDP and GTP. In the presence of Mg2+ cations, which can bind to the di- and tri-phosphate moieties of the purine nucleotides, this inhibitory effects is reduced.[2] The activation of UCP1 is induced by long-chain fatty acids, which are liberated as a result of adrenergic stimulation.[3] Specifically, when norepinephrine is released by the sympathetic nervous system, it binds and stimulates the β3-adrenergic receptor of brown adipocytes, leading to the activation of adenylyl cyclase (AC) and an increase in the level of cAMP. The released messenger cAMP stimulates PKA, which phosphorylates and activates the lipases HSL as well as ATGL that subsequently degrade tri- and di-glycerides resulting in the release of free fatty acids. The long-chain, fatty acids get oxidized and activate UCP1, which thereby initiates the uncoupling of mitochondrial respiration from ATP synthesis by causing a proton leak. [4] [5] However, the exact mode of action of UCP1 has not yet been completely understood.[6] [7]
During the first 30 years after the discovery of UCP1, it was believed that brown adipose tissue containing UCP1 can only be found in placental mammals, while it has since then been proven to be also present in marsupials, fish and amphibians.[8] [9] Current research focuses on the question whether the different types of UCP1 share common characteristics and are evolutionary related. What has already been found out is that the murine as well as human UCP1 can be activated by fatty acids or retinoids and inhibited by purine nucleotides. However, there is also proof for interspecies differences, such as the discovery that rodent UCP1 orthologs exhibit a basal proton conductance, whereas human uncoupling proteins have selectively lost the basal proton conductance.[10]


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References

  1. Rousset S, Alves-Guerra M-C, Mozo J, Miroux B, Cassard-Doulcier A-M, Bouillaud F, Ricquier D (2004) The biology of mitochondrial uncoupling proteins. Diabetes 53(Suppl 1):S130-35.
  2. Klingenspor M, Fromme T (2012) Brown adipose tissue. In: Symonds ME, editor. Adipose tissue biology. Springer, New York. p39-69.
  3. Fedorenko A, Lishko PV, Kirichok Y (2012) Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 151:400-13.
  4. Cannon B, Nedergaard J (2004) Brown adipose tissue: Function and physiological significance. Physiol Rev 84:277-359.
  5. Klingenspor M (2003) Cold-induced recruitment of brown adipose tissue thermogenesis. Exp Physiol 88:141-48.
  6. Bertholet AM, Kirichok Y (2016) UCP1: A transporter for H+ and fatty acid anions. Biochimie 1-7.
  7. Li Y, Fromme T, Schweizer S, Schottl T, Klingenspor M (2014) Taking control over intracellular fatty acid levels is essential for the analysis of thermogenic function in cultured primary brown and brite/beige adipocytes. EMBO Reports 15:1069-76.
  8. Hughes DA, Jastroch M, Stoneking M, Klingenspor M (2009) Molecular evolution of ucp1 and the evolutionary history of mammalian non-shivering thermogenesis. BMC Evol Biol 9:4.
  9. Klingenspor M, Fromme T, Hughes Jr DA, Manzke L, Polymeropoulos E, Riemann T, Trzcionka M, Hirschberg V, Jastroch M (2008) An ancient look at UCP1. Biochim Biophys Acta - Bioenergetics. 1777:637-41.
  10. Rodríguez-Sánchez L, Rial E (2016) The distinct bioenergetic properties of the human UCP1. Biochimie.


MitoPedia topics: Uncoupler