| Uncoupling proteins (UCP)
|
| According to the chemiosmotic hypothesis, the inner mitochondrial membrane is topologically closed. However, it has long been known that protons are transported into the matrix from the intermembrane space by routes other than the ATP synthase complex. Much of the BMR is now thought to be mainly due to inner membrane components called uncoupling proteins (UCP). The first discovered was uncoupling protein-1 (UCP1), formerly known as thermogenin, which is found exclusively in brown adipose tissue. Brown adipose tissue is abundant in the newborn and in some adult mammals, and it is brown because of its high content of mitochondria. In humans, brown adipose tissue is abundant in infants, but it gradually diminishes and is barely detectable in adults. The sole function of UCP1 is to provide body heat during cold stress in the young and in some adult animals and during hibernation. It accomplishes this by uncoupling the proton gradient, thereby generating heat (thermogenesis) instead of ATP.
|
| Four additional uncoupling proteins are expressed by the human genome, UCP2, UCP3, UCP4 and UCP5. While UCP1 is exclusive to brown adipose tissue, UCP2 is expressed ubiquitously, UCP3 is mainly expressed in skeletal muscle, and UCP4 and UCP5 are expressed in the brain. Except for UCP1, the physiological functions of these proteins are not well understood, but could be of profound significance in our understanding of such health issues as diabetes, obesity, cancer, thyroid disease and aging. As uncouplers, they have been linked to a number of fundamental functions. For example, there is strong evidence that obesity induces the synthesis of UCP2 in β-cells of the pancreas. This may play a role in the β-cell dysfunction found in type 2 diabetes, because it lowers the intracellular concentration of ATP, which is required for secretion of insulin. The thyroid hormone (T3) has been shown to stimulate thermogenesis in rats by promoting the synthesis of UCP3 in skeletal muscle. Of course, the common fever that is induced by infectious organisms is probably due to uncoupling by UCPs, but the mechanism is unknown. The UCP system may also be important in regulating the membrane potential.
|
|
