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Cytochrome c and apoptosis

As mentioned in one of my last posts, cytochrome c is a small protein, essential for mitochondrial respiratory chain, where it acts as an electron carrier between the complex III and complex IV. Besides this very important function, cytochrome c is also an important activator of programmed cell death, or apoptosis; more specifically, it is an activator of the intrinsic pathway of apoptosis. Because of this dual role, cytochrome c is often classified as "a central molecule for life in our oxygen world, and simultaneously a key that opens the door to death."

While apoptosis is a form of cell death, it is a fundamental mechanism for keeping the homeostasis of our body. In fact, when a cell accumulates irreparable damage (in DNA or in another biomolecule), when placed in an environment where it may be potentially dangerous to the remaining cells (shortage of nutrients, detachment from the surrounding cells, deprivation of growth factors, infection, autoreactive leukocytes, etc.), or when it is not important in the body (natural selection of neurons, for example) tends to commit suicide - apoptosis. This obvious idea, but at the same time strange, suggests something that I often refer in my classes, that is the fact that multicellular organisms must be regarded not as a living being composed of many cells, but as a living community, where each cell has its role, and lives in community with the others.

Apoptosis is a complex process that involves many mediators and that ultimately leads to the activation of enzymes that promote cell self-digestion. Caspases are a class of proteases that plays a key role in the apoptotic response. Overall, there are defined two apoptosis activation mechanisms: the intrinsic pathway and the extrinsic pathway. The intrinsic pathway is also sometimes referred to as pathway initiated by the cytochrome c, since this protein is the main actor in early apoptotic response. Several stimuli can lead to the release of cytochrome c from the intermembrane space into the cytosol. When this happens, it starts the activation of caspases. Under normal conditions cytochrome c does not abandon the intermembrane space, since it interacts with an existing glycerophospholipid in the inner mitochondrial membrane, cardiolipin. The high density of negative charges of the phospholipid electrostatically attracts the positively charged cytochrome c. In addition, a hydrophobic tail of the lipid is inserted in a hydrophobic cavity of the protein, enhancing the interaction between both molecules. It is the damage caused on cardiolipin which can make these interactions to be destroyed and the cytochrome c released.

Once in the cytosol, cytochrome c promotes the release of calcium stored in the endoplasmic reticulum, increasing the ion concentration in the cytosol. One of the functions of calcium is the stimulation of the release of more cytochrome c into the cytosol, thus causing a positive feedback loop. A further consequence of the presence of cytochrome c in the cytosol is the activation of caspase 9, which in turn activates caspases 3 and 7, and the fate of the cell is irreversible - death by apoptosis!

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Cellular respiration - Cytochrome c

The cytochrome c is a small protein with 104 amino acids and a mass of about 12 kDa (12.233 kDa in humans). As a consequence of its small size, it is highly conserved among different mammalian species; for example, the human cytochrome c is identical to the chimpanzee! It is a heteroprotein because beyond its amino acid, it contains also an heme group as a cofactor, which is bound to cysteines 14 and 17. It is a hydrophilic protein, highly soluble (solubility ~100 g/L), which is located in the mitochondrial intermembrane space, where it plays a key role in the mitochondrial respiratory chain, though it does not belong to any of the four complexes.
The function of the cytochrome c is to receive electrons from the complex III, and deliver them to the complex IV.  

To acomplish this function, its heme group, as any heme group, has an iron ion that can oscillate between two different oxidation states (Fe²⁺ and Fe³⁺). Since it has only 1 heme group, it can carry only one electron at a time. This feature has two very important consequences:

1. To deliver the 2 electrons from NADH or FADH₂ to O₂ in cellular respiration, it is required 2 molecules of cytochrome c.
2. O2, which is the final electron acceptor of the complex IV, receives one electron at a time, which means that it converted to, even temporarily (in most situations!), a free radical, which potentiates the oxidative stress.
Other functions less characterized of citocromoc are its involvement in catalytic hydroxylation reactions, aromatic oxidation and peroxidation. Also, it appears to be important to the catalytic activity of the nitrite reductase enzyme.

Finally, a very important characteristic of cytochrome c is that it can function as an activator of the intrinsic pathway of programmed cell death, a process referred to as apotose. Soon I will post more information on this subject...