|Cytochrome c, somatic|
Three-dimensional structure of cytochrome c (green) with a heme molecule coordinating a central Iron atom (orange).
|Symbols||; CYC; HCS; THC4|
|RNA expression pattern|
The cytochrome complex, or cyt c is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly water 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.
- Function 1
- Species distribution 2
- Classes 3
- Applications 4
- Role in apoptosis 5
- Extramitochondrial localization 6
- See also 7
- References 8
- Further reading 9
- Additional images 10
- External links 11
Cytochrome c is a component of the electron transport chain in mitochondria. The 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 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 such as 2,2-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), 2-keto-4-thiomethyl butyric acid and 4-aminoantipyrine.
Cytochrome c is involved in one form of nitrite reductase.
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
- The Cytochrome c Protein
- Apoptosis & Caspase 3 - PMAP The Proteolysis Map-animation
- UMich Orientation of Proteins in Membranes families/superfamily-78 - Calculated orientations of cytochromes c in the lipid bilayer
- Cytochrome c at the US National Library of Medicine Medical Subject Headings (MeSH)
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- Evans MJ, Scarpulla RC (1988). "The human somatic cytochrome c gene: two classes of processed pseudogenes demarcate a period of rapid molecular evolution". Proc. Natl. Acad. Sci. U.S.A. 85 (24): 9625–9.
- Passon PG, Hultquist DE (1972). "Soluble cytochrome b 5 reductase from human erythrocytes". Biochim. Biophys. Acta 275 (1): 62–73.
- Dowe RJ, Vitello LB, Erman JE (1984). "Sedimentation equilibrium studies on the interaction between cytochrome c and cytochrome c peroxidase". Arch. Biochem. Biophys. 232 (2): 566–73.
- Michel B, Bosshard HR (1984). "Spectroscopic analysis of the interaction between cytochrome c and cytochrome c oxidase". J. Biol. Chem. 259 (16): 10085–91.
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- Schneider J, Kroneck PM (2014). "Chapter 9: The Production of Ammonia by Multiheme Cytochromes c". In Kroneck PM, Torres ME. The Metal-Driven Biogeochemistry of Gaseous Compounds in the Environment. Metal Ions in Life Sciences 14. Springer. pp. 211–236.
"Cytochrome c - Homo sapiens (Human)". P99999. UniProt Consortium.
mass is 11,749 Daltons
- Margoliash E (October 1963). "Primary structure and evolution of cytochrome c". Proc. Natl. Acad. Sci. U.S.A. 50: 672–9.
- Amino acid sequences in cytochrome c proteins from different species, adapted from Strahler, Arthur; Science and Earth History, 1997. page 348.
- Lurquin PF, Stone L, Cavalli-Sforza LL (2007). Genes, culture, and human evolution: a synthesis. Oxford: Blackwell. p. 79.
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- Karu TI, Pyatibrat LV, Afanasyeva NI (2005). "Cellular effects of low power laser therapy can be mediated by nitric oxide". Lasers Surg Med 36 (4): 307–14.
- Liu X, Kim CN, Yang J, Jemmerson R, Wang X (July 1996). "Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c". Cell 86 (1): 147–57.
- Orrenius S, Zhivotovsky B (September 2005). "Cardiolipin oxidation sets cytochrome c free". Nat. Chem. Biol. 1 (4): 188–9.
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- Loo JF, Lau PM, Ho HP, Kong SK (2013). "An aptamer-based bio-barcode assay with isothermal recombinase polymerase amplification for cytochrome-c detection and anti-cancer drug screening". Talanta 115: 159-165.
- Waterhouse NJ, Trapani JA (2003). "A new quantitative assay for cytochrome c release in apoptotic cells.". Cell Death Differ. 10: 853-855.
- Soltys BJ, Andrews DW, Jemmerson R, Gupta RS (2001). "Cytochrome-C localizes in secretory granules in pancreas and anterior pituitary". Cell Biol. Int. 25 (4): 331–8.
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- Sadacharan SK, Singh B, Bowes T, Gupta RS (November 2005). "Localization of mitochondrial DNA encoded cytochrome c oxidase subunits I and II in rat pancreatic zymogen granules and pituitary growth hormone granules". Histochem. Cell Biol. 124 (5): 409–21.
- Soltys BJ, Gupta RS (2000). "Mitochondrial proteins at unexpected cellular locations: export of proteins from mitochondria from an evolutionary perspective". Int. Rev. Cytol. 194: 133–96.
- Soltys BJ, Gupta RS (May 1999). "Mitochondrial-matrix proteins at unexpected locations: are they exported?". Trends Biochem. Sci. 24 (5): 174–7.
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 caspase family of proteases is believed to be primary trigger leading to the onset of apoptosis. Measuring the amount of cytochrome c leaking from mitochondria to cytosol, and out of the cell to culture medium, is a sensitive method to monitor the degree 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 anterior pituitary, strong and specific presence of cytochrome-c was detected in zymogen granules and in growth hormone granules respectively. In the pancreas, cytochrome-c was also found in condensing 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.
The sustained elevation in 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 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 caspase 9, a cysteine protease. Caspase 9 can then go on to activate caspase 3 and caspase 7, which are responsible for destroying the cell from within.
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.
Cytochrome c binds to 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.
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.
Role in apoptosis
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 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.
- 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.
In 1991 R. P. Ambler recognized four classes of cytochrome c:
 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.