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!