Buniatov M. R., Dyomshina O. A., Osadcha O. V.

Oles Honchar Dnipropetrovsk National University

CITOCHROME C AND ITS FUNCTIONS

The cytochrome complex is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome  c  family of proteins. Cytochrome  c  is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an essential component of the electron transport chain, where it carries one electron. It is capable of undergoing oxidation and reduction, but does not bind 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  gene.

Cytochrome  c  is a component of the electron transport chain in mitochondria. The heme group of cytochrome  c  accepts electrons from the b-c1 complex and transfers electrons to the cytochrome oxidase complex. Cytochrome  c  is also involved in initiation of 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 hydroxylation and aromatic oxidation, and shows peroxidase activity by oxidation of various electron donors.

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 cladistics. Its primary structure consists of a chain of about 100 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 a chimpanzees (our closest relatives), but differs more from that of horses.

Cytochrome  c  is suspected to be the functional complex in so called LLLT: low-level laser therapy. In LLLT, red light and some near infra-red wavelengths penetrate the 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.

Cytochrome  c  is also an intermediate in 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 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 calcium levels precedes cytochrome  c  release from the mitochondria. The release of small amounts of cyt  c  leads to an interaction with the IP3 receptor (IP3R) on the 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.