Cytochrome c

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File:Cytochrome c image 2.png
Heme prosthetic group of cytochrome c, consisting of a rigid porphyrin ring coordinated with an iron atom.

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 highly water-soluble, unlike other cytochromes, 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.[1][2]

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),[3] makes it useful in studies of cladistics.[4] The cytochrome c molecule has been studied for the glimpse it gives into evolutionary biology.

Cytochrome c has a primary structure consisting of a chain of about 100 amino acids. Many higher-order organisms possess a chain of 104 amino acids.[5] The sequences of cytochrome c in humans is identical to that of chimpanzees (our closest relatives), but differs more from that of horses.[6]

Cytochrome c has an amino acid sequence that is highly conserved in eukaryotes, differing by only a few residues. In more than thirty species tested in one study, 34 of the 104 amino acids were conserved; identical at their characteristic position.[7] For example, human cytochrome oxidase reacts with wheat cytochrome c, in vitro; which held true for all pairs of species tested.[7] In addition, the redox potential of +0.25 volts is the same in all cytochrome c molecules studied.[7]


File:Tunafish cytochrome c crystals grown in microgravity.jpg
Tunafish cytochrome c crystals (~5 mm long) grown by liquid–liquid diffusion under microgravity conditions in outer space.[8]

Cytochrome c belongs to class I of the c-type cytochrome family[9] and contains a characteristic CXXCH (cysteine-any-any-cysteine-histidine) amino acid motif that binds heme.[10] This motif is located towards the N-terminus of the peptide chain and it contains a histidine as the fifth ligand of the heme iron. The sixth ligand is provided by a methionine residue found towards the C-terminus. The protein backbone is folded into five α-helices that are numbered α1-α5 from N-terminus to C-terminus. Helices α3, α4 and α5 are referred to as 50s, 60s and 70s helix respectively when referring to mitochondrial cytochrome c.[11]

Heme c

File:Heme c.svg
Structure of heme c

While most heme proteins are attached to the prosthetic group through iron ion ligation and tertiary interactions, the heme group of cytochrome c makes thioether bonds with two cysteine side chains of the protein.[12] One of the main properties of heme c, which allows cytochrome c to have variety of functions, is its ability to have different reduction potentials in nature. This property determines the kinetics and thermodynamics of an electron transfer reaction.[13]

Dipole moment

The dipole moment has an important role in orienting proteins to the proper directions and enhancing their abilities to bind to other molecules.[14][15] The dipole moment of cytochrome c is a result from a cluster of negatively charged amino acid side chains at the "back" of the enzyme.[15] Despite variations in the number of bound heme groups and variations in sequence, the dipole moment of vertebrate cytochromes c is remarkably conserved. For examples, vertebrate cytochromes c all have dipole moment of approximately 320 debye while cytochromes c of plants and insects have dipole moment of approximately 340 debye.[15]


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).[1]

Cytochrome c can also catalyze several redox 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.

A bacterial cytochrome c functions as a nitrite reductase.[16]

Role in apoptosis

Cytochrome c also has an intermediate role 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.[17]

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.

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.[18]

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.[19] 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.

Inhibition of apoptosis

One of the ways cell apoptosis is activated is by release of cytochrome c from the mitochondria into cytosol. A study has shown that cells are able to protect themselves from apoptosis by blocking the release of cytochrome c using Bcl-xL.[20] Another way that cells can control apoptosis is by phosphorylation of Tyr48 which would turn cytochrome c into an anti-apoptotic switch.[21]

As an antioxidative enzyme

File:Removal of O2- and H2O2 by cytochrome c.jpg
Removal of O2− and H2O2 by cytochrome c

Cytochrome c is known to play a role in the electron transport chain and cell apoptosis. However, a recent study has shown that it can also act as an antioxidative enzyme in the mitochondria; and it does so by removing superoxide (O2) and hydrogen peroxide (H2O2) from mitochondria.[22] Therefore, not only is cytochrome c required in the mitochondria for cell respiration, but it is also needed in the mitochondria to limit the production of O2 and H2O2.[22]

Extramitochondrial localization

Cytochrome c is widely believed to be localized solely in the mitochondrial intermembrane space under normal physiological conditions.[23] 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.[24] 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.[25][26] 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.[27] 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.[27] 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.[27] Besides cytochrome c, extramitochondrial localization has also been observed for large numbers of other proteins including those encoded by mitochondrial DNA.[28][29][30] This raises the possibility about existence of yet-unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.[30][31]


Superoxide detection

Peroxynitrous acid

Cytochrome c has been used to detect peroxide production in biological systems. As superoxide is produced, the number of oxidized cytochrome c3+ increases, and reduced cytochrome c2+ decreases.[32] However, superoxide is often produced with nitric oxide. In the presence of nitric oxide, the reduction of cytochrome c3+ is inhibited.[33] This leads to the oxidization of cytochrome c2+ to cytochrome c3+ by peroxynitrous acid, an intermediate made through the reaction of nitric oxide and superoxide.[33] Presence of peroxynitrite or H2O2 and nitrogen dioxide NO2 in the mitochondria can be lethal since they nitrate tyrosine residues of cytochrome c which leads to disruption of cytochrome c’s function as an electron carrier in the electron transfer chain.[34]

See also


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  3. "Cytochrome c – Homo sapiens (Human)". P99999. UniProt Consortium. mass is 11,749 Daltons
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  5. Amino acid sequences in cytochrome c proteins from different species, adapted from Strahler, Arthur; Science and Earth History, 1997. page 348.
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  16. 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. doi:10.1007/978-94-017-9269-1_9.
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  18. Orrenius S, Zhivotovsky B (September 2005). "Cardiolipin oxidation sets cytochrome c free". Nature Chemical Biology. 1 (4): 188–9. doi:10.1038/nchembio0905-188. PMID 16408030.
  19. Boehning D, Patterson RL, Sedaghat L, Glebova NO, Kurosaki T, Snyder SH (December 2003). "Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis". Nature Cell Biology. 5 (12): 1051–61. doi:10.1038/ncb1063. PMID 14608362.
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  32. McCord JM, Fridovich I (November 1969). "Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein)". The Journal of Biological Chemistry. 244 (22): 6049–55. PMID 5389100.
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Further reading

  • Kumarswamy R, Chandna S (February 2009). "Putative partners in Bax mediated cytochrome-c release: ANT, CypD, VDAC or none of them?". Mitochondrion. 9 (1): 1–8. doi:10.1016/j.mito.2008.10.003. PMID 18992370.
  • Skulachev VP (February 1998). "Cytochrome c in the apoptotic and antioxidant cascades". FEBS Letters. 423 (3): 275–80. doi:10.1016/S0014-5793(98)00061-1. PMID 9515723.
  • Mannella CA (1998). "Conformational changes in the mitochondrial channel protein, VDAC, and their functional implications". Journal of Structural Biology. 121 (2): 207–18. doi:10.1006/jsbi.1997.3954. PMID 9615439.
  • Ferri KF, Jacotot E, Blanco J, Esté JA, Kroemer G (2000). "Mitochondrial control of cell death induced by HIV-1-encoded proteins". Annals of the New York Academy of Sciences. 926: 149–64. doi:10.1111/j.1749-6632.2000.tb05609.x. PMID 11193032.
  • Britton RS, Leicester KL, Bacon BR (October 2002). "Iron toxicity and chelation therapy". International Journal of Hematology. 76 (3): 219–28. doi:10.1007/BF02982791. PMID 12416732.
  • Haider N, Narula N, Narula J (December 2002). "Apoptosis in heart failure represents programmed cell survival, not death, of cardiomyocytes and likelihood of reverse remodeling". Journal of Cardiac Failure. 8 (6 Suppl): S512–7. doi:10.1054/jcaf.2002.130034. PMID 12555167.
  • Castedo M, Perfettini JL, Andreau K, Roumier T, Piacentini M, Kroemer G (December 2003). "Mitochondrial apoptosis induced by the HIV-1 envelope". Annals of the New York Academy of Sciences. 1010: 19–28. doi:10.1196/annals.1299.004. PMID 15033690.
  • Ng S, Smith MB, Smith HT, Millett F (November 1977). "Effect of modification of individual cytochrome c lysines on the reaction with cytochrome b5". Biochemistry. 16 (23): 4975–8. doi:10.1021/bi00642a006. PMID 199233.
  • Lynch SR, Sherman D, Copeland RA (January 1992). "Cytochrome c binding affects the conformation of cytochrome a in cytochrome c oxidase". The Journal of Biological Chemistry. 267 (1): 298–302. PMID 1309738.
  • Garber EA, Margoliash E (February 1990). "Interaction of cytochrome c with cytochrome c oxidase: an understanding of the high- to low-affinity transition". Biochimica et Biophysica Acta. 1015 (2): 279–87. doi:10.1016/0005-2728(90)90032-Y. PMID 2153405.
  • Bedetti CD (May 1985). "Immunocytochemical demonstration of cytochrome c oxidase with an immunoperoxidase method: a specific stain for mitochondria in formalin-fixed and paraffin-embedded human tissues". The Journal of Histochemistry and Cytochemistry. 33 (5): 446–52. doi:10.1177/33.5.2580882. PMID 2580882.
  • Tanaka Y, Ashikari T, Shibano Y, Amachi T, Yoshizumi H, Matsubara H (June 1988). "Construction of a human cytochrome c gene and its functional expression in Saccharomyces cerevisiae". Journal of Biochemistry. 103 (6): 954–61. PMID 2844747.
  • Evans MJ, Scarpulla RC (December 1988). "The human somatic cytochrome c gene: two classes of processed pseudogenes demarcate a period of rapid molecular evolution". Proceedings of the National Academy of Sciences of the United States of America. 85 (24): 9625–9. doi:10.1073/pnas.85.24.9625. PMC 282819. PMID 2849112.
  • Passon PG, Hultquist DE (July 1972). "Soluble cytochrome b 5 reductase from human erythrocytes". Biochimica et Biophysica Acta. 275 (1): 62–73. doi:10.1016/0005-2728(72)90024-2. PMID 4403130.
  • Dowe RJ, Vitello LB, Erman JE (August 1984). "Sedimentation equilibrium studies on the interaction between cytochrome c and cytochrome c peroxidase". Archives of Biochemistry and Biophysics. 232 (2): 566–73. doi:10.1016/0003-9861(84)90574-5. PMID 6087732.
  • Michel B, Bosshard HR (August 1984). "Spectroscopic analysis of the interaction between cytochrome c and cytochrome c oxidase". The Journal of Biological Chemistry. 259 (16): 10085–91. PMID 6088481.
  • Broger C, Nałecz MJ, Azzi A (October 1980). "Interaction of cytochrome c with cytochrome bc1 complex of the mitochondrial respiratory chain". Biochimica et Biophysica Acta. 592 (3): 519–27. doi:10.1016/0005-2728(80)90096-1. PMID 6251869.
  • Smith HT, Ahmed AJ, Millett F (May 1981). "Electrostatic interaction of cytochrome c with cytochrome c1 and cytochrome oxidase". The Journal of Biological Chemistry. 256 (10): 4984–90. PMID 6262312.
  • Geren LM, Millett F (October 1981). "Fluorescence energy transfer studies of the interaction between adrenodoxin and cytochrome c". The Journal of Biological Chemistry. 256 (20): 10485–9. PMID 6270113.
  • Favre B, Zolnierowicz S, Turowski P, Hemmings BA (June 1994). "The catalytic subunit of protein phosphatase 2A is carboxyl-methylated in vivo". The Journal of Biological Chemistry. 269 (23): 16311–7. PMID 8206937.
  • Gao B, Eisenberg E, Greene L (July 1996). "Effect of constitutive 70-kDa heat shock protein polymerization on its interaction with protein substrate". The Journal of Biological Chemistry. 271 (28): 16792–7. doi:10.1074/jbc.271.28.16792. PMID 8663341.

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