Sunday, June 29, 2014

Metabolic map about circadian rhythms

Sunday, June 22, 2014

Uncoupling proteins

The uncoupling proteins (UCPs) are proteins that, as their name indicates, will decouple, that means, separate processes that occur in normal conditions associated with one another. I am talking about the transport of electrons along the mitochondrial respiratory chain, and ATP synthesis. What happens is that, under normal conditions, if one of the processes stops, the other will be blocked. The presence of UCPs allows a process to can occur even in the absence of the other. Basically they are proteins of the inner mitochondrial membrane that will allow the return to the matrix of the H+ accumulated in the intermembrane space without passing through ATP synthase. 
Thus, it will continue to occur the transport of electrons in the respiratory chain, but this process will no longer be solely dependent on the synthesis of ATP. There are different isoforms of UCPs… UCP1, also known as thermogenin serves to produce heat in brown adipose tissue, thereby helping to maintain body heat in newborns and during hibernation, for example. The UCP2 is a protein essentially involved in the production of heat in the muscle; however, recent papers have suggested that this protein may also be important to regulate the levels of reactive oxygen species in mitochondria. The UCP3 is still not as well characterized, but it is thought that it may be related to the regulation of the levels of reactive oxygen species in skeletal muscle and cardiac muscle.

Monday, June 9, 2014

Cellular respiration - Complex IV

Complex IV is the last complex of the mitochondrial respiratory chain complex, being designated as cytochrome c oxidase. It is a large transmembrane complex, which like the other complexes is located in the inner mitochondrial membrane. Its function is to accept the electrons from the molecules of cytochrome c, and transfer them to their final acceptor, the molecular oxygen. So, oxygen is converted into water, because in addition of being reduced, it binds H+ ions.

Structurally, the complex IV has 14 subunits (about 204 kDa), among which we can highlight several proteins with metal cofactors. Specifically, it is important to note the existence of two heme-containing cytochromes (a and a3) and two copper-containing centers (CuA and CuB). The center CuB and cytochrome a3 form together the oxygen reduction site. Among the 14 subunits, only 3 are encoded by mitochondrial DNA.

As happens with the complex I and complex III, complex IV also pumps protons from the matrix to the intermembrane space. However, in this case for each 2 electrons that pass through the complex, only 2 H+ are pumped to the intermembrane space. By the way, here it is a tip that I usually teach to my students, for them to remember the amount of H+ that is pumped during the respiratory chain. This trick only works if know a little bit about football (soccer). You must think that the tactic is 4-4-2, as the transport of H+ takes place in just this way: 4 in complex I, 4 in complex III and 2 in complex IV! :)

There are several diseases associated with mutations in genes coding for components of complex IV, and that usually translates to very serious consequences for individuals (those are the most severe mitochondrial diseases that are described). Examples include Leigh syndrome, sensorineural deafness, leukodystrophies, etc. These diseases tend to manifest during the early stages of life and especially compromise the functioning of organs such as the brain or heart. The explanation for this is simple, because we are talking about malfunctions of the main source of ATP in most of our cells. Therefore, organs with high energy needs are potentially the most affected ones.

Monday, June 2, 2014

Cellular respiration - Complex III

The complex III of the mitochondrial respiratory chain is called bc1 complex or ubiquinone:cytochrome c oxidoreductase. Its main function is to receive electrons from ubiquinone and transfer them to cytochrome c. In fact, complex III will accept electrons from 2 reduced ubiquinone (ubiquinol) molecules, wich means that it will receive 4 electrons. However, one of those ubiquinone molecules (now oxidized) will receive again 2 electrons. Thus, although complex III receives 4 electrons, it will only transfer 2 to cytochrome c. this process is often called Q-cycle, since ubiquinone can also be mentioned as coenzyme Q.
Cytochrome c is a small soluble protein present in the intermembrane space. Its function is to receive electrons from complex III and transfer them to complex IV, that means, it is not part of any complex of the respiratory chain in particular. It has a very important feature, which is the fact that it can only accept one electron, which means that for the complex III to exert its function it needs to transfer 2 electrons of a molecule of ubiquinone (since it is reduced it is known as ubiquinol) to two molecules of cytochrome c. This will have obvious implications for the formation of reactive oxygen species, but I'll leave that subject for a future post ...

From the structural point of view, the complex III presents a dimeric structure composed of two monomers with at least 11 subunits. Of these, three of each of the monomers have a direct role in the transfer of electrons along the complex. Of all the subunits, we should highlight the presence of cytochrome b and Rieske protein, which is a protein with a Fe-S center, more specifically 2Fe-2S.
As it happens with complex I (and IV , as I will develop in a future post), the flow of the electrons through complex III liberates energy, and that energy is used to actively transport H+ from the matrix to the intermembrane space, creating an electrochemical gradient, which subsequently will be involved in the synthesis of ATP. In this case, for each 2 electrons that are transported along complex III, 4H+ are transferred to the intermembrane space.
The complex III is inhibited, for example, by antimycin A. When it is inhibited, it can lead to the leakage of electrons that can reduce molecular oxygen, originating superoxide anion. Therefore, besides the potentially severe consequences associated with the inhibition of the respiratory chain, oxidative stress may also occur.