Thermogenin

Overview
Thermogenin (called uncoupling protein by its discoverers and now known as uncoupling protein 1, or UCP1) is an uncoupling protein found in the mitochondria of brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis. Non-shivering thermogenesis is the primary means of heat generation in hibernating mammals and in human infants.

Mechanism
The molecular mechanism of UCP1 mediated uncoupling is reasonably well understood; UCP1 provides an alternative pathway by which protons can reenter the mitochondrial matrix, short-circuiting the 'proton circuit' linking the respiratory chain to the ATP synthase (which generates ATP for the cell) and allowing respiration (and hence heat production) to proceed in the absence of ATP synthesis. UCP1 is related to other mitochondrial metabolite transporters such as the adenine nucleotide translocator a proton channel in the mitochondrial inner membrane that permits the translocation of protons from the mitochondrial intermembrane space to the mitochondrial matrix. UCP1 is restricted to brown fat where it provides a mechanism for the enormous heat generating capacity of the tissue.

UCP1 is activated in the brown fat cell by fatty acids that are liberated by the following pathway: Sympathetic nervous system terminals release noradrenaline onto a beta3 membrane receptor. This activates adenylyl cyclase which catalyses the conversion of ATP to cyclic AMP (cAMP). cAMP activates protein kinase A causing its active C subunits to be freed from its regulatory R subunits. Active protein kinase A in turn phosphorylates triacylglycerol lipase, thereby activating it. The lipase converts triacylglycerols into free fatty acids which activate UCP1, overriding the inhibition causes by cytoplasmic ATP. At the termination of thermogenesis, the mitochondria oxidize away the residual fatty acids, UCP1 inactivates and the cell resumes its normal energy-conserving mode.

History
Uncoupling protein 1 was discovered in 1979 - see and was first cloned in 1988.

Uncoupling protein two (UCP2), a homolog of UCP1, was identified in 1997.

In the past decade three additional homologs of UCP1 have been identified, including UCP3, UCP4, and BMCP1 (also known as UCP5).