Cytochrome c

The cytochrome complex, or cyt c is a small is_associated_with::hemeprotein found loosely associated with the inner membrane of the is_associated_with::mitochondrion. It belongs to the is_associated_with::cytochrome c family of proteins. Cytochrome c is a highly water soluble protein, unlike other is_associated_with::cytochromes, with a solubility of about 100 g/L and is an essential component of the is_associated_with::electron transport chain, where it carries one electron. It is capable of undergoing is_associated_with::oxidation and reduction, but does not bind is_associated_with::oxygen. It transfers electrons between Complexes III (Coenzyme Q - Cyt C reductase) and IV (Cyt C oxidase). In humans, cytochrome c is encoded by the CYCS is_associated_with::gene.

Function
Cytochrome c is a component of the is_associated_with::electron transport chain in mitochondria. The is_associated_with::heme group of cytochrome c accepts electrons from the bc1 complex and transfers electrons to the complex IV. Cytochrome c is also involved in initiation of is_associated_with::apoptosis. Upon release of cytochrome c to the cytoplasm, the protein binds apoptotic protease activating factor-1 (Apaf-1).

Cytochrome c can catalyze several reactions such as is_associated_with::hydroxylation and is_associated_with::aromatic is_associated_with::oxidation, and shows is_associated_with::peroxidase activity by oxidation of various electron donors such as 2,2-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (is_associated_with::ABTS), 2-keto-4-thiomethyl butyric acid and 4-aminoantipyrine.

Cytochrome c is involved in one form of is_associated_with::nitrite reductase.

Species distribution
Cytochrome c is a highly conserved protein across the spectrum of species, found in plants, animals, and many unicellular organisms. This, along with its small size (molecular weight about 12,000 daltons), makes it useful in studies of is_associated_with::cladistics. Its primary structure consists of a chain of about 100 is_associated_with::amino acids. Many higher order organisms possess a chain of 104 amino acids. The cytochrome c molecule has been studied for the glimpse it gives into evolutionary biology. Its amino acid sequence is highly conserved in mammals differing by only a few residues. For example, the sequences of cytochrome c in humans is identical to that of chimpanzees (our closest relatives), but differs more from that of horses.

Classes
In 1991 R. P. Ambler recognized four classes of cytochrome c:


 * Class I includes the lowspin soluble cytochrome c of mitochondria and bacteria. It has the heme-attachment site towards the N terminus of histidine and the sixth ligand provided by a methionine residue towards the C terminus.
 * Class II includes the highspin cytochrome c'. It has the heme-attachment site closed to the N terminus of histidine.
 * Class III comprises the low redox potential multiple heme cytochromes. The heme c groups are structurally and functionally nonequivalent and present different redox potentials in the range 0 to -400 mV.
 * Class IV was originally created to hold the complex proteins that have other prosthetic groups as well as heme c.

Applications
Cytochrome c is suspected to be the functional complex in so called LLLT: is_associated_with::Low-level laser therapy. In LLLT, red light and some near infra-red wavelengths penetrate tissue in order to increase cellular regeneration. Light of this wavelength appears capable of increasing activity of cytochrome c, thus increasing metabolic activity and freeing up more energy for the cells to repair the tissue.

Role in apoptosis


Cytochrome c is also an intermediate in is_associated_with::apoptosis, a controlled form of cell death used to kill cells in the process of development or in response to infection or DNA damage.

Cytochrome c binds to is_associated_with::cardiolipin in the inner mitochondrial membrane, thus anchoring its presence and keeping it from releasing out of the mitochondria and initiating apoptosis. While the initial attraction between cardiolipin and cytochrome c is electrostatic due to the extreme positive charge on cytochrome c, the final interaction is hydrophobic, where a hydrophobic tail from cardiolipin inserts itself into the hydrophobic portion of cytochrome c.

During the early phase of apoptosis, mitochondrial ROS production is stimulated, and cardiolipin is oxidized by a peroxidase function of the cardiolipin–cytochrome c complex. The hemoprotein is then detached from the mitochondrial inner membrane and can be extruded into the soluble cytoplasm through pores in the outer membrane.

The sustained elevation in is_associated_with::calcium levels precedes cyt c release from the mitochondria. The release of small amounts of cyt c leads to an interaction with the IP3 receptor (IP3R) on the is_associated_with::endoplasmic reticulum (ER), causing ER calcium release. The overall increase in calcium triggers a massive release of cyt c, which then acts in the positive feedback loop to maintain ER calcium release through the IP3Rs. This explains how the ER calcium release can reach cytotoxic levels. This release of cytochrome c in turn activates is_associated_with::caspase 9, a cysteine is_associated_with::protease. Caspase 9 can then go on to activate is_associated_with::caspase 3 and is_associated_with::caspase 7, which are responsible for destroying the cell from within.

Extramitochondrial localization
Cytochrome c is widely believed to be localized solely in the mitochondrial intermembrane space under normal physiological conditions. The release of cytochrome-c from mitochondria to the cytosol, where it activates the is_associated_with::caspase family of is_associated_with::proteases is believed to be primary trigger leading to the onset of apoptosis. However, detailed immunoelectron microscopic studies with rat tissues sections employing cytochrome c-specific antibodies provide compelling evidence that cytochrome-c under normal cellular conditions is also present at extramitochondrial locations. In pancreatic acinar cells and the is_associated_with::anterior pituitary, strong and specific presence of cytochrome-c was detected in is_associated_with::zymogen granules and in is_associated_with::growth hormone granules respectively. In the pancreas, cytochrome-c was also found in condensing is_associated_with::vacuoles and in the acinar lumen. The extramitochondrial localization of cytochrome c was shown to be specific as it was completely abolished upon adsorption of the primary antibody with the purified cytochrome c. The presence of cytochrome-c outside of mitochondria at specific location under normal physiological conditions raises important questions concerning its cellular function and translocation mechanism. Besides cytochrome c, extramitochondrial localization has also been observed for large numbers of other proteins including those encoded by mitochondrial DNA. This raises the possibility about existence of yet-unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.