Cytochrome c

Cytochrome c

Cytochrome c, somatic
Three-dimensional structure of cytochrome c (green) with a heme molecule coordinating a central Iron atom (orange).
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols  ; CYC; HCS; THC4
External IDs GeneCards:
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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.[1][2]


  • 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).[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.[3]

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

External links

Additional images

  • Kumarswamy R, Chandna S (2009). "Putative partners in Bax mediated cytochrome-c release: ANT, CypD, VDAC or none of them?". Mitochondrion 9 (1): 1–8.  
  • Skulachev VP (1998). "Cytochrome c in the apoptotic and antioxidant cascades". FEBS Lett. 423 (3): 275–80.  
  • Mannella CA (1998). "Conformational changes in the mitochondrial channel protein, VDAC, and their functional implications". J. Struct. Biol. 121 (2): 207–18.  
  • Ferri KF, Jacotot E, Blanco J, Esté JA, Kroemer G (2000). "Mitochondrial control of cell death induced by HIV-1-encoded proteins". Ann. N. Y. Acad. Sci. 926: 149–64.  
  • Britton RS, Leicester KL, Bacon BR (2002). "Iron toxicity and chelation therapy". Int. J. Hematol. 76 (3): 219–28.  
  • Haider N, Narula N, Narula J (2002). "Apoptosis in heart failure represents programmed cell survival, not death, of cardiomyocytes and likelihood of reverse remodeling". J. Card. Fail. 8 (6 Suppl): S512–7.  
  • Castedo M, Perfettini JL, Andreau K, Roumier T, Piacentini M, Kroemer G (December 2003). "Mitochondrial apoptosis induced by the HIV-1 envelope". Ann. N. Y. Acad. Sci. 1010: 19–28.  
  • Ng S, Smith MB, Smith HT, Millett F (1977). "Effect of modification of individual cytochrome c lysines on the reaction with cytochrome b5". Biochemistry 16 (23): 4975–8.  
  • Lynch SR, Sherman D, Copeland RA (1992). "Cytochrome c binding affects the conformation of cytochrome a in cytochrome c oxidase". J. Biol. Chem. 267 (1): 298–302.  
  • Garber EA, Margoliash E (1990). "Interaction of cytochrome c with cytochrome c oxidase: an understanding of the high- to low-affinity transition". Biochim. Biophys. Acta 1015 (2): 279–87.  
  • Bedetti CD (1985). "Immunocytochemical demonstration of cytochrome c oxidase with an immunoperoxidase method: a specific stain for mitochondria in formalin-fixed and paraffin-embedded human tissues". J. Histochem. Cytochem. 33 (5): 446–52.  
  • 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". J. Biochem. 103 (6): 954–61.  
  • 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.  
  • Broger C, Nałecz MJ, Azzi A (1980). "Interaction of cytochrome c with cytochrome bc1 complex of the mitochondrial respiratory chain". Biochim. Biophys. Acta 592 (3): 519–27.  
  • Smith HT, Ahmed AJ, Millett F (1981). "Electrostatic interaction of cytochrome c with cytochrome c1 and cytochrome oxidase". J. Biol. Chem. 256 (10): 4984–90.  
  • Geren LM, Millett F (1981). "Fluorescence energy transfer studies of the interaction between adrenodoxin and cytochrome c". J. Biol. Chem. 256 (20): 10485–9.  
  • Favre B, Zolnierowicz S, Turowski P, Hemmings BA (1994). "The catalytic subunit of protein phosphatase 2A is carboxyl-methylated in vivo". J. Biol. Chem. 269 (23): 16311–7.  
  • Gao B, Eisenberg E, Greene L (1996). "Effect of constitutive 70-kDa heat shock protein polymerization on its interaction with protein substrate". J. Biol. Chem. 271 (28): 16792–7.  

Further reading

  1. ^ a b "Entrez Gene: cytochrome c". 
  2. ^ Tafani M, Karpinich NO, Hurster KA, Pastorino JG, Schneider T, Russo MA, Farber JL (March 2002). "Cytochrome c release upon Fas receptor activation depends on translocation of full-length bid and the induction of the mitochondrial permeability transition". J. Biol. Chem. 277 (12): 10073–82.  
  3. ^ 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.  
  4. ^ "Cytochrome c - Homo sapiens (Human)". P99999. UniProt Consortium. mass is 11,749 Daltons 
  5. ^ Margoliash E (October 1963). "Primary structure and evolution of cytochrome c". Proc. Natl. Acad. Sci. U.S.A. 50: 672–9.  
  6. ^ Amino acid sequences in cytochrome c proteins from different species, adapted from Strahler, Arthur; Science and Earth History, 1997. page 348.
  7. ^ Lurquin PF, Stone L, Cavalli-Sforza LL (2007). Genes, culture, and human evolution: a synthesis. Oxford: Blackwell. p. 79.  
  8. ^ Ambler RP (May 1991). "Sequence variability in bacterial cytochromes c". Biochim. Biophys. Acta 1058 (1): 42–7.  
  9. ^ 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.  
  10. ^ 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.  
  11. ^ Orrenius S, Zhivotovsky B (September 2005). "Cardiolipin oxidation sets cytochrome c free". Nat. Chem. Biol. 1 (4): 188–9.  
  12. ^ 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". Nat. Cell Biol. 5 (12): 1051–61.  
  13. ^ Neupert W (1997). "Protein import into mitochondria". Annu. Rev. Biochem. 66: 863–917.  
  14. ^ Kroemer G, Dallaporta B, Resche-Rigon M (1998). "The mitochondrial death/life regulator in apoptosis and necrosis". Annu. Rev. Physiol. 60: 619–42.  
  15. ^ 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.  
  16. ^ Waterhouse NJ, Trapani JA (2003). "A new quantitative assay for cytochrome c release in apoptotic cells.". Cell Death Differ. 10: 853-855.  
  17. ^ a b c 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.  
  18. ^ Gupta RS, Ramachandra NB, Bowes T, Singh B (2008). "Unusual cellular disposition of the mitochondrial molecular chaperones Hsp60, Hsp70 and Hsp10". Novartis Found. Symp. 291: 59–68; discussion 69–73, 137–40.  
  19. ^ 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.  
  20. ^ a b 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.  
  21. ^ Soltys BJ, Gupta RS (May 1999). "Mitochondrial-matrix proteins at unexpected locations: are they exported?". Trends Biochem. Sci. 24 (5): 174–7.  


See also

Cytochrome c is widely believed to be localized solely in the mitochondrial intermembrane space under normal physiological conditions.[13] 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.[14] 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. [15][16] 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.[17] 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.[17] 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.[17] Besides cytochrome c, extramitochondrial localization has also been observed for large numbers of other proteins including those encoded by mitochondrial DNA.[18][19][20] This raises the possibility about existence of yet-unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.[20][21]

Extramitochondrial localization

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.[12] 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.[11]

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.[10]

Overview of signal transduction pathways involved in apoptosis.

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.[9]


  • 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:[8]


[7] 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.[6]