Editing Oxidative phosphorylation (section)

== Eukaryotic electron transport chains ==
{{further|Electron transport chain|Chemiosmosis}}
Many [[catabolic]] biochemical processes, such as [[glycolysis]], the [[citric acid cycle]], and [[beta oxidation]], produce the reduced [[Cofactor (biochemistry)|coenzyme]] [[NADH]]. This coenzyme contains electrons that have a high [[Standard electrode potential|transfer potential]]; in other words, they will release a large amount of energy upon oxidation. However, the cell does not release this energy all at once, as this would be an uncontrollable reaction. Instead, the electrons are removed from NADH and passed to oxygen through a series of enzymes that each release a small amount of the energy. This set of enzymes, consisting of complexes I through IV, is called the electron transport chain and is found in the [[inner membrane of the mitochondrion]]. [[succinic acid|Succinate]] is also oxidized by the electron transport chain, but feeds into the pathway at a different point.

In [[eukaryote]]s, the enzymes in this electron transport system use the energy released from O<sub>2</sub> by NADH to pump [[proton]]s across the inner membrane of the mitochondrion. This causes protons to build up in the [[intermembrane space]], and generates an [[electrochemical gradient]] across the membrane. The energy stored in this potential is then used by ATP synthase to produce ATP. Oxidative phosphorylation in the eukaryotic mitochondrion is the best-understood example of this process. The mitochondrion is present in almost all eukaryotes, with the exception of anaerobic protozoa such as ''[[Trichomonas vaginalis]]'' that instead reduce protons to hydrogen in a remnant mitochondrion called a [[hydrogenosome]].<ref>{{cite journal | vauthors = Boxma B, de Graaf RM, van der Staay GW, van Alen TA, Ricard G, Gabaldón T, van Hoek AH, Moon-van der Staay SY, Koopman WJ, van Hellemond JJ, Tielens AG, Friedrich T, Veenhuis M, Huynen MA, Hackstein JH | title = An anaerobic mitochondrion that produces hydrogen | journal = Nature | volume = 434 | issue = 7029 | pages = 74–79 | date = March 2005 | pmid = 15744302 | doi = 10.1038/nature03343 | s2cid = 4401178 | bibcode = 2005Natur.434...74B }}</ref>

{| class="wikitable" style="margin-left: auto; margin-right: auto; text-align:center"
|+ Typical respiratory enzymes and substrates in eukaryotes.
|-
!Respiratory enzyme
![[redox|Redox pair]]
! [[Standard electrode potential#Non-standard condition|Midpoint potential]]&nbsp;
(Volts)
|-
| [[NADH dehydrogenase]]
| [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]] / [[Nicotinamide adenine dinucleotide|NADH]]
| −0.32<ref name=Pedersen>Medical CHEMISTRY Compendium. By Anders Overgaard Pedersen and Henning Nielsen. Aarhus University. 2008</ref>
|-
| [[Succinate dehydrogenase]]
| [[Flavin mononucleotide|FMN]] or [[Flavin adenine dinucleotide|FAD]] / FMNH<sub>2</sub> or FADH<sub>2</sub>
| −0.20<ref name=Pedersen/>
|-
| [[Coenzyme Q - cytochrome c reductase|Cytochrome bc<sub>1</sub> complex]]
| [[Coenzyme Q10]]<sub>ox</sub> / Coenzyme Q10<sub>red</sub>
| +0.06<ref name=Pedersen/>
|-
| Cytochrome bc<sub>1</sub> complex
| [[Cytochrome b]]<sub>ox</sub> / Cytochrome b<sub>red</sub>
| +0.12<ref name=Pedersen/>
|-
|align=left|[[Cytochrome c oxidase|Complex IV]]
| [[Cytochrome c]]<sub>ox</sub> / Cytochrome c<sub>red</sub>
| +0.22<ref name=Pedersen/>
|-
|align=left|Complex IV
| [[Cytochrome a]]<sub>ox</sub> / Cytochrome a<sub>red</sub>
| +0.29<ref name=Pedersen/>
|-
|align=left|Complex IV
| O<sub>2</sub> / HO<sup>−</sup>
| +0.82<ref name=Pedersen/>
|-
|align=left colspan=3|<span style="font-size:87%;"> Conditions: pH = 7</span><ref name=Pedersen/>
|}

=== NADH-coenzyme Q oxidoreductase (complex I) ===
[[File:Complex I.svg|350px|thumb|right|Complex I or [[NADH dehydrogenase|NADH-Q oxidoreductase]]. The abbreviations are discussed in the text. In all diagrams of respiratory complexes in this article, the matrix is at the bottom, with the intermembrane space above.{{image reference needed|date=December 2022}}]]

[[NADH dehydrogenase|NADH-coenzyme Q oxidoreductase]], also known as ''NADH dehydrogenase'' or ''complex I'', is the first protein in the electron transport chain.<ref name=Hirst>{{cite journal | vauthors = Hirst J | title = Energy transduction by respiratory complex I--an evaluation of current knowledge | journal = Biochemical Society Transactions | volume = 33 | issue = Pt 3 | pages = 525–529 | date = June 2005 | pmid = 15916556 | doi = 10.1042/BST0330525 }}</ref> Complex I is a giant [[enzyme]] with the mammalian complex I having 46 subunits and a molecular mass of about 1,000 [[atomic mass unit|kilodaltons]] (kDa).<ref name=Lenaz2006>{{cite journal | vauthors = Lenaz G, Fato R, Genova ML, Bergamini C, Bianchi C, Biondi A | title = Mitochondrial Complex I: structural and functional aspects | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1757 | issue = 9–10 | pages = 1406–1420 | year = 2006 | pmid = 16828051 | doi = 10.1016/j.bbabio.2006.05.007 | doi-access = free }}</ref> The structure is known in detail only from a bacterium;<ref name="thermophilus1">{{cite journal | vauthors = Sazanov LA, Hinchliffe P | title = Structure of the hydrophilic domain of respiratory complex I from Thermus thermophilus | journal = Science | volume = 311 | issue = 5766 | pages = 1430–1436 | date = March 2006 | pmid = 16469879 | doi = 10.1126/science.1123809 | s2cid = 1892332 | doi-access = free | bibcode = 2006Sci...311.1430S }}</ref><ref name="Ecoli">{{cite journal | vauthors = Efremov RG, Baradaran R, Sazanov LA | title = The architecture of respiratory complex I | journal = Nature | volume = 465 | issue = 7297 | pages = 441–445 | date = May 2010 | pmid = 20505720 | doi = 10.1038/nature09066 | s2cid = 4372778 | bibcode = 2010Natur.465..441E }}</ref> in most organisms the complex resembles a boot with a large "ball" poking out from the membrane into the mitochondrion.<ref>{{cite journal | vauthors = Baranova EA, Holt PJ, Sazanov LA | title = Projection structure of the membrane domain of Escherichia coli respiratory complex I at 8 A resolution | journal = Journal of Molecular Biology | volume = 366 | issue = 1 | pages = 140–154 | date = February 2007 | pmid = 17157874 | doi = 10.1016/j.jmb.2006.11.026 }}</ref><ref>{{cite journal | vauthors = Friedrich T, Böttcher B | title = The gross structure of the respiratory complex I: a Lego System | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1608 | issue = 1 | pages = 1–9 | date = January 2004 | pmid = 14741580 | doi = 10.1016/j.bbabio.2003.10.002 | doi-access = free }}</ref> The genes that encode the individual proteins are contained in both the [[cell nucleus]] and the [[mitochondrial genome]], as is the case for many enzymes present in the mitochondrion.

The reaction that is catalyzed by this enzyme is the two electron oxidation of [[Nicotinamide adenine dinucleotide|NADH]] by [[coenzyme Q10]] or ''ubiquinone'' (represented as Q in the equation below), a lipid-soluble [[quinone]] that is found in the mitochondrion membrane:

{{NumBlk|:|<chem>NADH + Q + 5H+_{matrix} -> NAD+ + QH2 + 4H+_{intermembrane}</chem>|{{EquationRef|1}}}}

The start of the reaction, and indeed of the entire electron chain, is the binding of a NADH molecule to complex I and the donation of two electrons. The electrons enter complex I via a [[prosthetic group]] attached to the complex, [[flavin mononucleotide]] (FMN). The addition of electrons to FMN converts it to its reduced form, FMNH<sub>2</sub>. The electrons are then transferred through a series of iron–sulfur clusters: the second kind of prosthetic group present in the complex.<ref name="thermophilus1"/> There are both [2Fe–2S] and [4Fe–4S] iron–sulfur clusters in complex I.

As the electrons pass through this complex, four protons are pumped from the matrix into the intermembrane space. Exactly how this occurs is unclear, but it seems to involve [[conformational change]]s in complex I that cause the protein to bind protons on the N-side of the membrane and release them on the P-side of the membrane.<ref>{{cite journal | vauthors = Hirst J | title = Towards the molecular mechanism of respiratory complex I | journal = The Biochemical Journal | volume = 425 | issue = 2 | pages = 327–339 | date = December 2009 | pmid = 20025615 | doi = 10.1042/BJ20091382 }}</ref> Finally, the electrons are transferred from the chain of iron–sulfur clusters to a ubiquinone molecule in the membrane.<ref name=Hirst/> Reduction of ubiquinone also contributes to the generation of a proton gradient, as two protons are taken up from the matrix as it is reduced to [[ubiquinol]] (QH<sub>2</sub>).

=== Succinate-Q oxidoreductase (complex II) ===
[[File:Complex II.svg|250px|thumb|right|Complex II: [[Succinate - coenzyme Q reductase|Succinate-Q oxidoreductase]].]]

[[Succinate - coenzyme Q reductase|Succinate-Q oxidoreductase]], also known as ''complex II'' or ''succinate dehydrogenase'', is a second entry point to the electron transport chain.<ref>{{cite journal | vauthors = Cecchini G | title = Function and structure of complex II of the respiratory chain | journal = Annual Review of Biochemistry | volume = 72 | pages = 77–109 | year = 2003 | pmid = 14527321 | doi = 10.1146/annurev.biochem.72.121801.161700 }}</ref> It is unusual because it is the only enzyme that is part of both the citric acid cycle and the electron transport chain. Complex II consists of four protein subunits and contains a bound [[flavin adenine dinucleotide]] (FAD) cofactor, iron–sulfur clusters, and a [[heme]] group that does not participate in electron transfer to coenzyme Q, but is believed to be important in decreasing production of reactive oxygen species.<ref>{{cite journal | vauthors = Yankovskaya V, Horsefield R, Törnroth S, Luna-Chavez C, Miyoshi H, Léger C, Byrne B, Cecchini G, Iwata S | title = Architecture of succinate dehydrogenase and reactive oxygen species generation | journal = Science | volume = 299 | issue = 5607 | pages = 700–704 | date = January 2003 | pmid = 12560550 | doi = 10.1126/science.1079605 | s2cid = 29222766 | bibcode = 2003Sci...299..700Y }}</ref><ref>{{cite journal | vauthors = Horsefield R, Iwata S, Byrne B | title = Complex II from a structural perspective | journal = Current Protein & Peptide Science | volume = 5 | issue = 2 | pages = 107–118 | date = April 2004 | pmid = 15078221 | doi = 10.2174/1389203043486847 }}</ref> It oxidizes [[succinic acid|succinate]] to [[Fumaric acid|fumarate]] and reduces ubiquinone. As this reaction releases less energy than the oxidation of NADH, complex II does not transport protons across the membrane and does not contribute to the proton gradient.

{{NumBlk|:|<chem>{Succinate} + Q -> {Fumarate} + QH2</chem>|{{EquationRef|2}}}}

In some eukaryotes, such as the [[parasitic worm]] ''[[Large roundworm of pigs|Ascaris suum]]'', an enzyme similar to complex II, fumarate reductase (menaquinol:fumarate
oxidoreductase, or QFR), operates in reverse to oxidize ubiquinol and reduce fumarate. This allows the worm to survive in the anaerobic environment of the [[large intestine]], carrying out anaerobic oxidative phosphorylation with fumarate as the electron acceptor.<ref>{{cite journal | vauthors = Kita K, Hirawake H, Miyadera H, Amino H, Takeo S | title = Role of complex II in anaerobic respiration of the parasite mitochondria from Ascaris suum and Plasmodium falciparum | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1553 | issue = 1–2 | pages = 123–139 | date = January 2002 | pmid = 11803022 | doi = 10.1016/S0005-2728(01)00237-7 | doi-access = free }}</ref> Another unconventional function of complex II is seen in the [[malaria]] parasite ''[[Plasmodium falciparum]]''. Here, the reversed action of complex II as an oxidase is important in regenerating ubiquinol, which the parasite uses in an unusual form of [[pyrimidine]] biosynthesis.<ref>{{cite journal | vauthors = Painter HJ, Morrisey JM, Mather MW, Vaidya AB | title = Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum | journal = Nature | volume = 446 | issue = 7131 | pages = 88–91 | date = March 2007 | pmid = 17330044 | doi = 10.1038/nature05572 | s2cid = 4421676 | bibcode = 2007Natur.446...88P }}</ref>

=== Electron transfer flavoprotein-Q oxidoreductase ===
[[Electron-transferring-flavoprotein dehydrogenase|Electron transfer flavoprotein-ubiquinone oxidoreductase]] (ETF-Q oxidoreductase), also known as ''electron transferring-flavoprotein dehydrogenase'', is a third entry point to the electron transport chain. It is an enzyme that accepts electrons from [[electron-transferring flavoprotein]] in the mitochondrial matrix, and uses these electrons to reduce ubiquinone.<ref>{{cite journal | vauthors = Ramsay RR, Steenkamp DJ, Husain M | title = Reactions of electron-transfer flavoprotein and electron-transfer flavoprotein: ubiquinone oxidoreductase | journal = The Biochemical Journal | volume = 241 | issue = 3 | pages = 883–892 | date = February 1987 | pmid = 3593226 | pmc = 1147643 | doi = 10.1042/bj2410883 }}</ref> This enzyme contains a [[Flavin group|flavin]] and a [4Fe–4S] cluster, but, unlike the other respiratory complexes, it attaches to the surface of the membrane and does not cross the lipid bilayer.<ref>{{cite journal | vauthors = Zhang J, Frerman FE, Kim JJ | title = Structure of electron transfer flavoprotein-ubiquinone oxidoreductase and electron transfer to the mitochondrial ubiquinone pool | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 44 | pages = 16212–16217 | date = October 2006 | pmid = 17050691 | pmc = 1637562 | doi = 10.1073/pnas.0604567103 | doi-access = free | bibcode = 2006PNAS..10316212Z }}</ref>

{{NumBlk|:|<chem>ETF_{red}{} + Q -> ETF_{ox}{} + QH2</chem>|{{EquationRef|3}}}}

In mammals, this metabolic pathway is important in [[beta oxidation]] of [[fatty acid]]s and catabolism of [[amino acid]]s and [[choline]], as it accepts electrons from multiple [[acetyl-CoA]] dehydrogenases.<ref>{{cite journal | vauthors = Ikeda Y, Dabrowski C, Tanaka K | title = Separation and properties of five distinct acyl-CoA dehydrogenases from rat liver mitochondria. Identification of a new 2-methyl branched chain acyl-CoA dehydrogenase | journal = The Journal of Biological Chemistry | volume = 258 | issue = 2 | pages = 1066–1076 | date = January 1983 | pmid = 6401712 | doi = 10.1016/S0021-9258(18)33160-0 | url = http://www.jbc.org/cgi/reprint/258/2/1066 | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20070929111233/http://www.jbc.org/cgi/reprint/258/2/1066 | archive-date = 29 September 2007 }}</ref><ref>{{cite journal | vauthors = Ruzicka FJ, Beinert H | title = A new iron-sulfur flavoprotein of the respiratory chain. A component of the fatty acid beta oxidation pathway | journal = The Journal of Biological Chemistry | volume = 252 | issue = 23 | pages = 8440–8445 | date = December 1977 | pmid = 925004 | doi = 10.1016/S0021-9258(19)75238-7 | url = http://www.jbc.org/cgi/reprint/252/23/8440.pdf | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20070927135249/http://www.jbc.org/cgi/reprint/252/23/8440.pdf | archive-date = 2007-09-27 }}</ref> In plants, ETF-Q oxidoreductase is also important in the metabolic responses that allow survival in extended periods of darkness.<ref>{{cite journal | vauthors = Ishizaki K, Larson TR, Schauer N, Fernie AR, Graham IA, Leaver CJ | title = The critical role of Arabidopsis electron-transfer flavoprotein:ubiquinone oxidoreductase during dark-induced starvation | journal = The Plant Cell | volume = 17 | issue = 9 | pages = 2587–2600 | date = September 2005 | pmid = 16055629 | pmc = 1197437 | doi = 10.1105/tpc.105.035162 | bibcode = 2005PlanC..17.2587I }}</ref>

=== Q-cytochrome c oxidoreductase (complex III) ===
[[File:Complex III reaction.svg|420px|thumb|right|The two electron transfer steps in complex III: [[Coenzyme Q - cytochrome c reductase|Q-cytochrome c oxidoreductase]]. After each step, Q (in the upper part of the figure) leaves the enzyme.]]

[[Coenzyme Q - cytochrome c reductase|Q-cytochrome c oxidoreductase]] is also known as ''cytochrome c reductase'', ''cytochrome bc<sub>1</sub> complex'', or simply ''complex III''.<ref>{{cite journal | vauthors = Berry EA, Guergova-Kuras M, Huang LS, Crofts AR | title = Structure and function of cytochrome bc complexes | journal = Annual Review of Biochemistry | volume = 69 | pages = 1005–1075 | year = 2000 | pmid = 10966481 | doi = 10.1146/annurev.biochem.69.1.1005 | url = http://www.life.illinois.edu/crofts/pdf_files/ARB_review.pdf | url-status = live | citeseerx = 10.1.1.319.5709 | archive-url = https://web.archive.org/web/20151228224336/http://www.life.illinois.edu/crofts/pdf_files/ARB_review.pdf | archive-date = 2015-12-28 }}</ref><ref>{{cite journal | vauthors = Crofts AR | title = The cytochrome bc1 complex: function in the context of structure | journal = Annual Review of Physiology | volume = 66 | pages = 689–733 | year = 2004 | pmid = 14977419 | doi = 10.1146/annurev.physiol.66.032102.150251 }}</ref> In mammals, this enzyme is a [[protein dimer|dimer]], with each subunit complex containing 11 protein subunits, an [2Fe-2S] iron–sulfur cluster and three [[cytochrome]]s: one [[cytochrome]] c<sub>1</sub> and two b [[cytochromes]].<ref>{{cite journal | vauthors = Iwata S, Lee JW, Okada K, Lee JK, Iwata M, Rasmussen B, Link TA, Ramaswamy S, Jap BK | title = Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex | journal = Science | volume = 281 | issue = 5373 | pages = 64–71 | date = July 1998 | pmid = 9651245 | doi = 10.1126/science.281.5373.64 | bibcode = 1998Sci...281...64I }}</ref> A cytochrome is a kind of electron-transferring protein that contains at least one [[heme]] group. The iron atoms inside complex III's heme groups alternate between a reduced ferrous (+2) and oxidized ferric (+3) state as the electrons are transferred through the protein.

The reaction catalyzed by complex III is the oxidation of one molecule of [[ubiquinol]] and the reduction of two molecules of [[cytochrome c]], a heme protein loosely associated with the mitochondrion. Unlike coenzyme Q, which carries two electrons, cytochrome c carries only one electron.

{{NumBlk|:|<chem>QH2{} + 2 Cyt\, c_{ox}{} + 2H+_{matrix} -> Q{} + 2 Cyt\, c_{red}{} + 4H+_{intermembrane}</chem>|{{EquationRef|4}}}}

As only one of the electrons can be transferred from the QH<sub>2</sub> donor to a cytochrome c acceptor at a time, the reaction mechanism of complex III is more elaborate than those of the other respiratory complexes, and occurs in two steps called the [[Q cycle]].<ref>{{cite journal | vauthors = Trumpower BL | title = The protonmotive Q cycle. Energy transduction by coupling of proton translocation to electron transfer by the cytochrome bc1 complex | journal = The Journal of Biological Chemistry | volume = 265 | issue = 20 | pages = 11409–11412 | date = July 1990 | pmid = 2164001 | doi = 10.1016/S0021-9258(19)38410-8 | url = http://www.jbc.org/cgi/reprint/265/20/11409.pdf | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20070927135240/http://www.jbc.org/cgi/reprint/265/20/11409.pdf | archive-date = 2007-09-27 }}</ref> In the first step, the enzyme binds three substrates, first, QH<sub>2</sub>, which is then oxidized, with one electron being passed to the second substrate, cytochrome c. The two protons released from QH<sub>2</sub> pass into the intermembrane space. The third substrate is Q, which accepts the second electron from the QH<sub>2</sub> and is reduced to Q<sup>.−</sup>, which is the [[semiquinone|ubisemiquinone]] [[free radical]]. The first two substrates are released, but this ubisemiquinone intermediate remains bound. In the second step, a second molecule of QH<sub>2</sub> is bound and again passes its first electron to a cytochrome c acceptor. The second electron is passed to the bound ubisemiquinone, reducing it to QH<sub>2</sub> as it gains two protons from the mitochondrial matrix. This QH<sub>2</sub> is then released from the enzyme.<ref>{{cite journal | vauthors = Hunte C, Palsdottir H, Trumpower BL | title = Protonmotive pathways and mechanisms in the cytochrome bc1 complex | journal = FEBS Letters | volume = 545 | issue = 1 | pages = 39–46 | date = June 2003 | pmid = 12788490 | doi = 10.1016/S0014-5793(03)00391-0 | s2cid = 13942619 | doi-access = free | bibcode = 2003FEBSL.545...39H }}</ref>

As coenzyme Q is reduced to ubiquinol on the inner side of the membrane and oxidized to ubiquinone on the other, a net transfer of protons across the membrane occurs, adding to the proton gradient.<ref name=Schultz/> The rather complex two-step mechanism by which this occurs is important, as it increases the efficiency of proton transfer. If, instead of the Q cycle, one molecule of QH<sub>2</sub> were used to directly reduce two molecules of cytochrome c, the efficiency would be halved, with only one proton transferred per cytochrome c reduced.<ref name=Schultz/>

=== Cytochrome c oxidase (complex IV) ===
{{further|cytochrome c oxidase}}
[[File:Complex IV.svg|thumb|right|Complex IV: [[cytochrome c oxidase]].]]

[[Cytochrome c oxidase]], also known as ''complex IV'', is the final protein complex in the electron transport chain.<ref>{{cite journal | vauthors = Calhoun MW, Thomas JW, Gennis RB | title = The cytochrome oxidase superfamily of redox-driven proton pumps | journal = Trends in Biochemical Sciences | volume = 19 | issue = 8 | pages = 325–330 | date = August 1994 | pmid = 7940677 | doi = 10.1016/0968-0004(94)90071-X }}</ref> The mammalian enzyme has an extremely complicated structure and contains 13 subunits, two heme groups, as well as multiple metal ion cofactors&nbsp;– in all, three atoms of [[copper]], one of [[magnesium]] and one of [[zinc]].<ref>{{cite journal | vauthors = Tsukihara T, Aoyama H, Yamashita E, Tomizaki T, Yamaguchi H, Shinzawa-Itoh K, Nakashima R, Yaono R, Yoshikawa S | title = The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 A | journal = Science | volume = 272 | issue = 5265 | pages = 1136–1144 | date = May 1996 | pmid = 8638158 | doi = 10.1126/science.272.5265.1136 | s2cid = 20860573 | bibcode = 1996Sci...272.1136T }}</ref>

This enzyme mediates the final reaction in the electron transport chain and transfers electrons to oxygen and hydrogen (protons), while pumping protons across the membrane.<ref>{{cite journal | vauthors = Yoshikawa S, Muramoto K, Shinzawa-Itoh K, Aoyama H, Tsukihara T, Shimokata K, Katayama Y, Shimada H | title = Proton pumping mechanism of bovine heart cytochrome c oxidase | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1757 | issue = 9–10 | pages = 1110–1116 | year = 2006 | pmid = 16904626 | doi = 10.1016/j.bbabio.2006.06.004 | doi-access = free }}</ref> The final [[electron acceptor]] oxygen is reduced to water in this step. Both the direct pumping of protons and the consumption of matrix protons in the reduction of oxygen contribute to the proton gradient. The reaction catalyzed is the oxidation of cytochrome c and the reduction of oxygen:

{{NumBlk|:|<chem>4 Cyt\,c_{red}{} + O2{} + 8H+_{matrix} -> 4 Cyt\,c_{ox}{} + 2H2O{} + 4H+_{intermembrane}</chem>|{{EquationRef|5}}}}

=== Alternative reductases and oxidases ===
Many eukaryotic organisms have electron transport chains that differ from the much-studied mammalian enzymes described above. For example, [[plant]]s have alternative NADH oxidases, which oxidize NADH in the cytosol rather than in the mitochondrial matrix, and pass these electrons to the ubiquinone pool.<ref>{{cite journal | vauthors = Rasmusson AG, Soole KL, Elthon TE | title = Alternative NAD(P)H dehydrogenases of plant mitochondria | journal = Annual Review of Plant Biology | volume = 55 | pages = 23–39 | year = 2004 | pmid = 15725055 | doi = 10.1146/annurev.arplant.55.031903.141720 }}</ref> These enzymes do not transport protons, and, therefore, reduce ubiquinone without altering the electrochemical gradient across the inner membrane.<ref>{{cite journal | vauthors = Menz RI, Day DA | title = Purification and characterization of a 43-kDa rotenone-insensitive NADH dehydrogenase from plant mitochondria | journal = The Journal of Biological Chemistry | volume = 271 | issue = 38 | pages = 23117–23120 | date = September 1996 | pmid = 8798503 | doi = 10.1074/jbc.271.38.23117 | s2cid = 893754 | doi-access = free }}</ref>

Another example of a divergent electron transport chain is the ''[[alternative oxidase]]'', which is found in [[plant]]s, as well as some [[fungus|fungi]], [[protist]]s, and possibly some animals.<ref>{{cite journal | vauthors = McDonald A, Vanlerberghe G | title = Branched mitochondrial electron transport in the Animalia: presence of alternative oxidase in several animal phyla | journal = IUBMB Life | volume = 56 | issue = 6 | pages = 333–341 | date = June 2004 | pmid = 15370881 | doi = 10.1080/1521-6540400000876 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sluse FE, Jarmuszkiewicz W | title = Alternative oxidase in the branched mitochondrial respiratory network: an overview on structure, function, regulation, and role | journal = Brazilian Journal of Medical and Biological Research = Revista Brasileira de Pesquisas Medicas e Biologicas | volume = 31 | issue = 6 | pages = 733–747 | date = June 1998 | pmid = 9698817 | doi = 10.1590/S0100-879X1998000600003 | doi-access = free }}</ref> This enzyme transfers electrons directly from ubiquinol to oxygen.<ref>{{cite journal | vauthors = Moore AL, Siedow JN | title = The regulation and nature of the cyanide-resistant alternative oxidase of plant mitochondria | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1059 | issue = 2 | pages = 121–140 | date = August 1991 | pmid = 1883834 | doi = 10.1016/S0005-2728(05)80197-5 }}</ref>

The electron transport pathways produced by these alternative NADH and ubiquinone oxidases have lower [[adenosine triphosphate|ATP]] yields than the full pathway. The advantages produced by a shortened pathway are not entirely clear. However, the alternative oxidase is produced in response to stresses such as cold, [[reactive oxygen species]], and infection by pathogens, as well as other factors that inhibit the full electron transport chain.<ref>{{cite journal | vauthors = Vanlerberghe GC, McIntosh L | title = ALTERNATIVE OXIDASE: From Gene to Function | journal = Annual Review of Plant Physiology and Plant Molecular Biology | volume = 48 | pages = 703–734 | date = June 1997 | pmid = 15012279 | doi = 10.1146/annurev.arplant.48.1.703 }}</ref><ref>{{cite journal | vauthors = Ito Y, Saisho D, Nakazono M, Tsutsumi N, Hirai A | title = Transcript levels of tandem-arranged alternative oxidase genes in rice are increased by low temperature | journal = Gene | volume = 203 | issue = 2 | pages = 121–129 | date = December 1997 | pmid = 9426242 | doi = 10.1016/S0378-1119(97)00502-7 }}</ref> Alternative pathways might, therefore, enhance an organism's resistance to injury, by reducing [[oxidative stress]].<ref>{{cite journal | vauthors = Maxwell DP, Wang Y, McIntosh L | title = The alternative oxidase lowers mitochondrial reactive oxygen production in plant cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 14 | pages = 8271–8276 | date = July 1999 | pmid = 10393984 | pmc = 22224 | doi = 10.1073/pnas.96.14.8271 | doi-access = free | bibcode = 1999PNAS...96.8271M }}</ref>

=== Organization of complexes ===
The original model for how the respiratory chain complexes are organized was that they diffuse freely and independently in the mitochondrial membrane.<ref name=Lenaz2001>{{cite journal | vauthors = Lenaz G | title = A critical appraisal of the mitochondrial coenzyme Q pool | journal = FEBS Letters | volume = 509 | issue = 2 | pages = 151–155 | date = December 2001 | pmid = 11741580 | doi = 10.1016/S0014-5793(01)03172-6 | s2cid = 46138989 | doi-access = free | bibcode = 2001FEBSL.509..151L }}</ref> However, recent data suggest that the complexes might form higher-order structures called supercomplexes or "[[respirasome]]s".<ref>{{cite journal | vauthors = Heinemeyer J, Braun HP, Boekema EJ, Kouril R | title = A structural model of the cytochrome C reductase/oxidase supercomplex from yeast mitochondria | journal = The Journal of Biological Chemistry | volume = 282 | issue = 16 | pages = 12240–12248 | date = April 2007 | pmid = 17322303 | doi = 10.1074/jbc.M610545200 | s2cid = 18123642 | doi-access = free }}</ref> In this model, the various complexes exist as organized sets of interacting enzymes.<ref>{{cite journal | vauthors = Schägger H, Pfeiffer K | title = Supercomplexes in the respiratory chains of yeast and mammalian mitochondria | journal = The EMBO Journal | volume = 19 | issue = 8 | pages = 1777–1783 | date = April 2000 | pmid = 10775262 | pmc = 302020 | doi = 10.1093/emboj/19.8.1777 }}</ref> These associations might allow channeling of substrates between the various enzyme complexes, increasing the rate and efficiency of electron transfer.<ref>{{cite journal | vauthors = Schägger H | title = Respiratory chain supercomplexes of mitochondria and bacteria | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1555 | issue = 1–3 | pages = 154–159 | date = September 2002 | pmid = 12206908 | doi = 10.1016/S0005-2728(02)00271-2 | doi-access = free }}</ref> Within such mammalian supercomplexes, some components would be present in higher amounts than others, with some data suggesting a ratio between complexes I/II/III/IV and the ATP synthase of approximately 1:1:3:7:4.<ref>{{cite journal | vauthors = Schägger H, Pfeiffer K | title = The ratio of oxidative phosphorylation complexes I-V in bovine heart mitochondria and the composition of respiratory chain supercomplexes | journal = The Journal of Biological Chemistry | volume = 276 | issue = 41 | pages = 37861–37867 | date = October 2001 | pmid = 11483615 | doi = 10.1074/jbc.M106474200 | url = http://www.jbc.org/cgi/content/full/276/41/37861 | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20070929115026/http://www.jbc.org/cgi/content/full/276/41/37861 | archive-date = 2007-09-29 }}</ref> However, the debate over this supercomplex hypothesis is not completely resolved, as some data do not appear to fit with this model.<ref name=Lenaz2006/><ref>{{cite journal | vauthors = Gupte S, Wu ES, Hoechli L, Hoechli M, Jacobson K, Sowers AE, Hackenbrock CR | title = Relationship between lateral diffusion, collision frequency, and electron transfer of mitochondrial inner membrane oxidation-reduction components | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 81 | issue = 9 | pages = 2606–2610 | date = May 1984 | pmid = 6326133 | pmc = 345118 | doi = 10.1073/pnas.81.9.2606 | doi-access = free | bibcode = 1984PNAS...81.2606G }}</ref>