View source for Cytochrome c

{{Infobox_gene}}
The '''cytochrome complex''', or '''cyt ''c''''' is a small [[hemeprotein]] found loosely associated with the [[inner mitochondrial membrane|inner membrane]] of the [[mitochondrion]]. It belongs to the [[cytochrome c family]] of proteins. Cytochrome c is highly water-soluble, unlike other [[cytochrome]]s, and is an essential component of the [[electron transport chain]], where it carries one electron. It is capable of undergoing [[oxidation]] and [[redox|reduction]], but does not bind [[oxygen]]. It transfers electrons between [[Coenzyme Q - cytochrome c reductase|Complexes III]] (Coenzyme Q – Cyt C reductase) and [[cytochrome c oxidase|IV]] (Cyt C oxidase).  In humans, cytochrome c is encoded by the ''CYCS'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: cytochrome c| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54205| accessdate = }}</ref><ref name="pmid11790791">{{cite journal | vauthors = Tafani M, Karpinich NO, Hurster KA, Pastorino JG, Schneider T, Russo MA, Farber JL | title = Cytochrome c release upon Fas receptor activation depends on translocation of full-length bid and the induction of the mitochondrial permeability transition | journal = The Journal of Biological Chemistry | volume = 277 | issue = 12 | pages = 10073–82 | date = Mar 2002 | pmid = 11790791 | doi = 10.1074/jbc.M111350200 }}</ref>

== 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 [[dalton (unit)|dalton]]s),<ref name="urlCytochrome c - Homo sapiens (Human)">{{cite web |url=http://www.uniprot.org/uniprot/P99999#section_seq |title=Cytochrome c – Homo sapiens (Human) |publisher=UniProt Consortium  |work=P99999 |quote=mass is 11,749 Daltons}}</ref> makes it useful in studies of [[cladistics]].<ref name="pmid14077496">{{cite journal | vauthors = Margoliash E | title = Primary structure and evolution of cytochrome c | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 50 | issue = 4 | pages = 672–9 | date = Oct 1963 | pmid = 14077496 | pmc = 221244 | doi = 10.1073/pnas.50.4.672 }}</ref> The cytochrome c molecule has been studied for the glimpse it gives into evolutionary biology.

Its primary structure consists of a chain of about 100 [[amino acid]]s.  Many higher-order organisms possess a chain of 104 amino acids.<ref name="indiana">[http://www.indiana.edu/~ensiweb/lessons/molb.ws.pdf Amino acid sequences in cytochrome c proteins from different species], adapted from Strahler, Arthur; Science and Earth History, 1997. page 348.</ref> The sequences of cytochrome c in humans is identical to that of chimpanzees (our closest relatives), but differs more from that of horses.<ref name="isbn978-1-4051-5089-7">{{cite book | vauthors = Lurquin PF, Stone L, Cavalli-Sforza LL | title = Genes, culture, and human evolution: a synthesis |publisher=Blackwell | location = Oxford | year = 2007 | page = 79 | isbn = 978-1-4051-5089-7 | url = https://books.google.com/books?id=zdeWdF_NQhEC&pg=PA79&lpg=PA79&dq=chimpanzee+rhesus+cytochrome+c#PPA79,M1}}</ref>

Its amino acid sequence is highly conserved in eukaryotes, differing by only a few residues. In more than thirty species, 34 of the 104 amino acids are conserved; identical at that position.<ref name="stryer">{{cite book  | last1 = Stryer | first1 = Lubert | name-list-format = vanc | title = Biochemistry | date = 1975 | publisher = W.H. Freeman and Company | location = San Francisco | isbn = 978-0-7167-0174-3 | page = 362 | edition = 1st }}</ref>  For example, human [[cytochrome oxidase]] reacts with wheat cytochrome ''c'', ''in vitro''; this is true for all pairs of species tested.<ref name="stryer"/> In addition the redox potential of +0.25 volts is the same in all cytochrome ''c'' molecules studied.<ref name="stryer"/>

== Structure ==

[[File:Tunafish cytochrome c crystals grown in microgravity.jpg|left|upright|thumb|Tunafish cytochrome c crystals (~5 mm long) grown by liquid–liquid diffusion under microgravity conditions in outer space.<ref>{{cite journal | doi = 10.1038/npjmgrav.2015.10 | title = Microgravity protein crystallization | journal = Npj Microgravity | volume = 1 | pages = 15010 | year = 2015 | last1 = McPherson | first1 = Alexander | last2 = Delucas | first2 = Lawrence James | name-list-format = vanc }}</ref>]]

All cytochrome c proteins contain a characteristic CXXCH (cysteine-any-any-cysteine-histidine) amino acid motif that binds heme. However, there are four classes of cytochrome c, each possessing a different fold.<ref name="pmid23341334">{{cite journal | vauthors = Mavridou DA, Ferguson SJ, Stevens JM | title = Cytochrome c assembly | journal = IUBMB Life | volume = 65 | issue = 3 | pages = 209–16 | year = 2013 | pmid = 23341334 | doi = 10.1002/iub.1123 }}</ref>

=== Classes ===

In 1991 R. P. Ambler recognized four classes of cytochrome c:<ref name="pmid1646017">{{cite journal | vauthors = Ambler RP | title = Sequence variability in bacterial cytochromes c | journal = Biochimica et Biophysica Acta | volume = 1058 | issue = 1 | pages = 42–7 | date = May 1991 | pmid = 1646017 | doi = 10.1016/S0005-2728(05)80266-X }}</ref>

*'''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 close 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.

=== Heme c ===

[[File:Heme c.svg|thumb|228x228px|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.<ref>{{cite journal | vauthors = Kang X, Carey J | title = Role of heme in structural organization of cytochrome c probed by semisynthesis | journal = Biochemistry | volume = 38 | issue = 48 | pages = 15944–51 | date = Nov 1999 | pmid = 10625461 | doi=10.1021/bi9919089}}</ref> 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.<ref>{{cite journal | vauthors = Zhao Y, Wang ZB, Xu JX | title = Effect of cytochrome c on the generation and elimination of O<sub>2</sub><sup>–</sup> and H<sub>2</sub>O<sub>2</sub> in mitochondria | journal = The Journal of Biological Chemistry | volume = 278 | issue = 4 | pages = 2356–60 | date = Jan 2003 | pmid = 12435729 | doi = 10.1074/jbc.M209681200 }}</ref>
                                                                     
=== 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.<ref>{{cite journal | vauthors = Koppenol WH, Margoliash E | title = The asymmetric distribution of charges on the surface of horse cytochrome c. Functional implications | journal = The Journal of Biological Chemistry | volume = 257 | issue = 8 | pages = 4426–37 | date = Apr 1982 | pmid = 6279635 }}</ref><ref name = "Koppenol_1982">{{cite journal | vauthors = Koppenol WH, Rush JD, Mills JD, Margoliash E | title = The dipole moment of cytochrome c | journal = Molecular Biology and Evolution | volume = 8 | issue = 4 | pages = 545–58 | date = Jul 1991 | pmid = 1656165 }}</ref> 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.<ref name="Koppenol_1982" /> 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.<ref name="Koppenol_1982" />

== Function ==

Cytochrome c is a component of the [[electron transport chain]] in mitochondria. The [[heme]] group of cytochrome c accepts electrons from the [[Complex III|bc<sub>1</sub> complex]] and transfers electrons to the [[cytochrome c oxidase|complex IV]]. Cytochrome c is also involved in initiation of [[apoptosis]]. Upon release of cytochrome c to the cytoplasm, the protein binds [[APAF1|apoptotic protease activating factor-1 (Apaf-1)]].<ref name="entrez"/>

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]].<ref>{{cite book | first1 = Jörg | last1 = Schneider | first2 = Peter M.H. | last2 =  Kroneck | editor1-first = Peter M.H. | editor1-last = Kroneck | editor2-first = Martha E. Sosa | editor2-last = Torres | title = The Metal-Driven Biogeochemistry of Gaseous Compounds in the Environment | series = Metal Ions in Life Sciences | volume = 14 | year = 2014 | publisher = Springer | chapter = Chapter 9: The Production of Ammonia by Multiheme Cytochromes c | pages = 211–236 | doi = 10.1007/978-94-017-9269-1_9 | name-list-format = vanc }}</ref>

=== 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.<ref name="pmid8689682">{{cite journal | vauthors = Liu X, Kim CN, Yang J, Jemmerson R, Wang X | title = Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c | journal = Cell | volume = 86 | issue = 1 | pages = 147–57 | date = Jul 1996 | pmid = 8689682 | doi = 10.1016/S0092-8674(00)80085-9 }}</ref>

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.<ref name="PMID16408030">{{cite journal | vauthors = Orrenius S, Zhivotovsky B | title = Cardiolipin oxidation sets cytochrome c free | journal = Nature Chemical Biology | volume = 1 | issue = 4 | pages = 188–9 | date = Sep 2005 | pmid = 16408030 | doi = 10.1038/nchembio0905-188 }}</ref>

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 [[Inositol triphosphate receptor|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.<ref name="pmid14608362">{{cite journal | vauthors = Boehning D, Patterson RL, Sedaghat L, Glebova NO, Kurosaki T, Snyder SH | title = Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis | journal = Nature Cell Biology | volume = 5 | issue = 12 | pages = 1051–61 | date = Dec 2003 | pmid = 14608362 | doi = 10.1038/ncb1063 }}</ref> 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-x<sub>L</sub>.<ref>{{cite journal | vauthors = Kharbanda S, Pandey P, Schofield L, Israels S, Roncinske R, Yoshida K, Bharti A, Yuan ZM, Saxena S, Weichselbaum R, Nalin C, Kufe D | title = Role for Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 13 | pages = 6939–42 | date = Jun 1997 | pmid = 9192670 | pmc=21263 | doi=10.1073/pnas.94.13.6939}}</ref> Another way that cells can control apoptosis is by phosphorylation of Tyr48 which would turn cytochrome c into an anti-apoptotic switch.<ref>{{cite journal | vauthors = García-Heredia JM, Díaz-Quintana A, Salzano M, Orzáez M, Pérez-Payá E, Teixeira M, De la Rosa MA, Díaz-Moreno I | title = Tyrosine phosphorylation turns alkaline transition into a biologically relevant process and makes human cytochrome c behave as an anti-apoptotic switch | journal = Journal of Biological Inorganic Chemistry | volume = 16 | issue = 8 | pages = 1155–68 | date = Dec 2011 | pmid = 21706253 | doi = 10.1007/s00775-011-0804-9 }}</ref>

=== As an antioxidative enzyme ===

[[File:Removal of O2- and H2O2 by cytochrome c.jpg|thumb|232x232px|Removal of O<sup>2−</sup> and H<sub>2</sub>O<sub>2</sub> 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]] (O<sub>2</sub><sup>–</sup>) and [[hydrogen peroxide]] (H<sub>2</sub>O<sub>2</sub>) from [[mitochondria]].<ref name = "Bowman_2008">{{cite journal | vauthors = Bowman SE, Bren KL | title = The chemistry and biochemistry of heme c: functional bases for covalent attachment | journal = Natural Product Reports | volume = 25 | issue = 6 | pages = 1118–30 | date = Dec 2008 | pmid = 19030605 | doi = 10.1039/b717196j | pmc=2654777}}</ref> 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 O<sub>2</sub><sup>–</sup> and H<sub>2</sub>O<sub>2</sub>.<ref name="Bowman_2008" />

== Extramitochondrial localization ==

Cytochrome c is widely believed to be localized solely in the mitochondrial intermembrane space under normal physiological conditions.<ref name="pmid9242927">{{cite journal | vauthors = Neupert W | title = Protein import into mitochondria | journal = Annual Review of Biochemistry | volume = 66 | issue =  | pages = 863–917 | year = 1997 | pmid = 9242927 | doi = 10.1146/annurev.biochem.66.1.863 }}</ref> 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.<ref name="pmid9558479">{{cite journal | vauthors = Kroemer G, Dallaporta B, Resche-Rigon M | title = The mitochondrial death/life regulator in apoptosis and necrosis | journal = Annual Review of Physiology | volume = 60 | issue =  | pages = 619–42 | year = 1998 | pmid = 9558479 | doi = 10.1146/annurev.physiol.60.1.619 }}</ref> 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.<ref name="pmid24054573">{{cite journal | vauthors = Loo JF, Lau PM, Ho HP, Kong SK | title = An aptamer-based bio-barcode assay with isothermal recombinase polymerase amplification for cytochrome-c detection and anti-cancer drug screening | journal = Talanta | volume = 115 | pages = 159–65 | date = Oct 2013 | pmid = 24054573 | doi = 10.1016/j.talanta.2013.04.051 }}</ref><ref name="pmid12815469">{{cite journal | vauthors = Waterhouse NJ, Trapani JA | title = A new quantitative assay for cytochrome c release in apoptotic cells | journal = Cell Death and Differentiation | volume = 10 | issue = 7 | pages = 853–5 | date = Jul 2003 | pmid = 12815469 | doi = 10.1038/sj.cdd.4401263 }}</ref>  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.<ref name="Soltys_2001">{{cite journal | vauthors = Soltys BJ, Andrews DW, Jemmerson R, Gupta RS | title = Cytochrome-C localizes in secretory granules in pancreas and anterior pituitary | journal = Cell Biology International | volume = 25 | issue = 4 | pages = 331–8 | year = 2001 | pmid = 11319839 | doi = 10.1006/cbir.2000.0651 }}</ref> 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 (anatomy)|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.<ref name="Soltys_2001" /> 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.<ref name="Soltys_2001" /> Besides cytochrome c, extramitochondrial localization has also been observed for large numbers of other proteins including those encoded by mitochondrial DNA.<ref name="pmid18575266">{{cite journal | vauthors = Gupta RS, Ramachandra NB, Bowes T, Singh B | title = Unusual cellular disposition of the mitochondrial molecular chaperones Hsp60, Hsp70 and Hsp10 | journal = Novartis Foundation Symposium | volume = 291 | issue =  | pages = 59–68; discussion 69–73, 137–40 | year = 2008 | pmid = 18575266 | doi = 10.1002/9780470754030.ch5 | isbn = 978-0-470-75403-0 | series = Novartis Foundation Symposia }}</ref><ref name="pmid16133117">{{cite journal | vauthors = Sadacharan SK, Singh B, Bowes T, Gupta RS | title = Localization of mitochondrial DNA encoded cytochrome c oxidase subunits I and II in rat pancreatic zymogen granules and pituitary growth hormone granules | journal = Histochemistry and Cell Biology | volume = 124 | issue = 5 | pages = 409–21 | date = Nov 2005 | pmid = 16133117 | doi = 10.1007/s00418-005-0056-2 }}</ref><ref name="Soltys_2000">{{cite journal | vauthors = Soltys BJ, Gupta RS | title = Mitochondrial proteins at unexpected cellular locations: export of proteins from mitochondria from an evolutionary perspective | journal = International Review of Cytology | volume = 194 | issue =  | pages = 133–96 | year = 2000 | pmid = 10494626 | doi = 10.1016/s0074-7696(08)62396-7 | isbn = 978-0-12-364598-2 | series = International Review of Cytology }}</ref> This raises the possibility about existence of yet-unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.<ref name="Soltys_2000" /><ref name="pmid10322429">{{cite journal | vauthors = Soltys BJ, Gupta RS | title = Mitochondrial-matrix proteins at unexpected locations: are they exported? | journal = Trends in Biochemical Sciences | volume = 24 | issue = 5 | pages = 174–7 | date = May 1999 | pmid = 10322429 | doi = 10.1016/s0968-0004(99)01390-0 }}</ref>

== Applications ==

=== Superoxide detection ===

[[File:Peroxynitrous-acid-2D.svg|thumb|[[Peroxynitrous acid]]]]

Cytochrome c has been used to detect peroxide production in biological systems. As superoxide is produced, the number of oxidized cytochrome c<sup>3+</sup> increases, and reduced cytochrome c<sup>2+</sup> decreases.<ref>{{cite journal | vauthors = McCord JM, Fridovich I | title = Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein) | journal = The Journal of Biological Chemistry | volume = 244 | issue = 22 | pages = 6049–55 | date = Nov 1969 | pmid = 5389100 }}</ref> However, superoxide is often produced with nitric oxide. In the presence of nitric oxide, the reduction of cytochrome c<sup>3+</sup> is inhibited.<ref name = "Thomson_1995">{{cite journal | vauthors = Thomson L, Trujillo M, Telleri R, Radi R | title = Kinetics of cytochrome c<sup>2+</sup> oxidation by peroxynitrite: implications for superoxide measurements in nitric oxide-producing biological systems | journal = Archives of Biochemistry and Biophysics | volume = 319 | issue = 2 | pages = 491–7 | date = Jun 1995 | pmid = 7786032 | doi = 10.1006/abbi.1995.1321 }}</ref> This leads to the oxidization of cytochrome c<sup>2+</sup> to cytochrome c<sup>3+</sup> by [[peroxynitrous acid]], an intermediate made through the reaction of nitric oxide and superoxide.<ref name="Thomson_1995" /> Presence of [[peroxynitrite]], H<sub>2</sub>O<sub>2</sub>, or [[nitrogen dioxide]] NO<sub>2</sub> 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.<ref>{{cite journal | vauthors = Domazou AS, Gebicka L, Didik J, Gebicki JL, van der Meijden B, Koppenol WH | title = The kinetics of the reaction of nitrogen dioxide with iron(II)- and iron(III) cytochrome c | journal = Free Radical Biology & Medicine | volume = 69 | pages = 172–80 | date = Apr 2014 | pmid = 24447894 | doi = 10.1016/j.freeradbiomed.2014.01.014 }}</ref>

== See also ==

* [[Cytochrome c oxidase]]

== References ==
{{Reflist|33em}}

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

== External links ==
{{Commons category|Cytochrome c}}
* [http://macromoleculeinsights.com/cytochromec.php The Cytochrome c Protein]
* [https://www.youtube.com/watch?v=l4D0YxGi5Ec Apoptosis & Caspase 3] – PMAP [[The Proteolysis Map]]-animation
* {{UMichOPM|families|superfamily|78}} – Calculated orientations of cytochromes c in the lipid bilayer
* {{MeshName|Cytochrome+c}}

{{PDB Gallery|geneid=54205}}
{{Electron transport chain}}
{{Fas apoptosis signaling pathway}}

[[Category:Cellular respiration]]
[[Category:Cytochromes]]
[[Category:Programmed cell death]]
[[Category:Peripheral membrane proteins]]
[[Category:Moonlighting proteins]]