View source for Oxidative phosphorylation

{{Short description|Metabolic pathway}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
[[File:Mitochondrial electron transport chain—Etc4.svg|thumb|400px|Oxidative phosphorylation is made up of two closely connected components: the [[electron transport chain]] and [[chemiosmosis]]. The electron transport chain in the [[cell (biology)|cell]] is the site of oxidative phosphorylation. The [[NADH]] and [[succinate]] generated in the [[citric acid cycle]] are oxidized, releasing the energy of O<sub>2</sub> to power the [[ATP synthase]].]]

[[File:Carbon Catabolism.png|thumb|420px|Carbon Catabolism pathway map for free energy including carbohydrate and lipid sources of energy, showing the upstream processes that feed precursors into the electron transport chain, shown here in a rainbow spectrum of colors in the bottom right of the diagram.]]

'''Oxidative phosphorylation'''<ref group="N">(UK {{IPAc-en|ɒ|k|ˈ|s|ɪ|d|.|ə|.|t|ɪ|v}}, US {{IPAc-en|ˈ|ɑː|k|.|s|ɪ|ˌ|d|eɪ|.|t|ɪ|v}}: {{cite news|url=https://dictionary.cambridge.org/dictionary/english/oxidative|title=Oxidative |website=Cambridge Dictionary|access-date=28 April 2018|url-status=live|archive-url=https://web.archive.org/web/20180124195701/https://dictionary.cambridge.org/dictionary/english/oxidative|archive-date=24 January 2018}}</ref> or '''electron transport-linked phosphorylation''' or '''terminal oxidation''', is the [[metabolic pathway]] in which [[Cell (biology)|cell]]s use [[enzyme]]s to [[Redox|oxidize]] [[nutrient]]s, thereby releasing chemical energy in order to produce [[adenosine triphosphate]] (ATP). In [[eukaryotes]], this takes place inside [[mitochondria]]. Almost all [[aerobic organism]]s carry out oxidative phosphorylation. This pathway is so pervasive because it releases more energy than [[fermentation (biochemistry)|fermentation]].

In [[aerobic respiration]], the energy stored in the chemical bonds of [[glucose]] is released by the cell in [[glycolysis]] and subsequently the [[citric acid cycle]], producing carbon dioxide and the energetic [[reducing agent|electron donors]] [[NADH]] and [[FADH₂]]. Oxidative phosphorylation uses these molecules and O<sub>2</sub> to [[ATP synthase|produce ATP]], which is used throughout the cell whenever energy is needed. During oxidative phosphorylation, electrons are transferred from the electron donors to a series of [[oxidizing agent|electron acceptors]] in a series of [[redox reaction]]s ending in oxygen, whose reaction releases half of the total energy.<ref name="Voet">{{Cite book |last=Voet |first=Donald |title=Biochemistry |last2=Voet |first2=Judith G. |date=2004 |publisher=Wiley |isbn=978-0-471-19350-0 |edition=3rd |series=Wiley international edition |location=New York, NY |page=804}}</ref>

In [[eukaryote]]s, these redox reactions are catalyzed by a series of [[protein complex]]es within the [[inner mitochondrial membrane]]; whereas, in [[prokaryote]]s, these proteins are located in the cell's [[Cell membrane|plasma membrane]]. These linked sets of proteins are called the [[electron transport chain]]. In mitochondria, five main protein complexes are involved, whereas prokaryotes have various other enzymes, using a variety of electron donors and acceptors.

The energy transferred by electrons flowing through this electron transport chain is used to transport [[proton]]s across the inner membrane. This generates [[potential energy]] in the form of a [[pH]] gradient and the resulting [[Membrane potential|electrical potential]] across this membrane. This store of energy is tapped when protons flow back across the membrane through [[ATP synthase]] in a process called [[chemiosmosis]]. The ATP synthase uses the energy to transform [[adenosine diphosphate]] (ADP) into adenosine triphosphate, in a [[phosphorylation]] reaction. The reaction is driven by the proton flow, which forces the [[rotation]] of a part of the enzyme. The ATP synthase is a rotary mechanical motor.

Although oxidative phosphorylation is a vital part of metabolism, it produces [[reactive oxygen species]] such as [[superoxide]] and [[hydrogen peroxide]], which lead to propagation of [[Radical (chemistry)|free radicals]], damaging cells and contributing to [[disease]] and, possibly, [[aging]] and [[senescence]]. The enzymes carrying out this metabolic pathway are also the target of many drugs and poisons that [[enzyme inhibitor|inhibit]] their activities.

== Chemiosmosis ==
{{further|Chemiosmosis|Bioenergetics}}
Oxidative phosphorylation works by using [[energy]]-releasing chemical reactions to drive energy-requiring reactions. The two sets of reactions are said to be ''coupled''. This means one cannot occur without the other. The chain of redox reactions driving the flow of electrons through the electron transport chain, from electron donors such as [[NADH]] to [[electron acceptor]]s such as [[oxygen]] and hydrogen (protons), is an [[exergonic]] process&nbsp;– it releases energy, whereas the synthesis of ATP is an [[endergonic]] process, which requires an input of energy. Both the electron transport chain and the ATP synthase are embedded in a membrane, and energy is transferred from the electron transport chain to the ATP synthase by movements of protons across this membrane, in a process called ''[[chemiosmosis]]''.<ref>{{cite journal | vauthors = Mitchell P, Moyle J | title = Chemiosmotic hypothesis of oxidative phosphorylation | journal = Nature | volume = 213 | issue = 5072 | pages = 137–139 | date = January 1967 | pmid = 4291593 | doi = 10.1038/213137a0 | s2cid = 4149605 | bibcode = 1967Natur.213..137M }}</ref> A current of protons is driven from the negative N-side of the membrane to the positive P-side through the proton-pumping enzymes of the electron transport chain. The movement of protons creates an [[electrochemical gradient]] across the membrane, which is called the [[proton-motive force]]. It has two components: a difference in proton concentration (a H<sup>+</sup> gradient, Δ[[pH]]) and a difference in [[electric potential]], with the N-side having a negative charge.<ref name=Dimroth2000>{{cite journal | vauthors = Dimroth P, Kaim G, Matthey U | title = Crucial role of the membrane potential for ATP synthesis by F(1)F(o) ATP synthases | journal = The Journal of Experimental Biology | volume = 203 | issue = Pt 1 | pages = 51–59 | date = January 2000 | pmid = 10600673 | doi = 10.1242/jeb.203.1.51 | bibcode = 2000JExpB.203...51D | url = http://jeb.biologists.org/cgi/reprint/203/1/51 | url-status = live | archive-url = https://web.archive.org/web/20070930044752/http://jeb.biologists.org/cgi/reprint/203/1/51 | archive-date = 30 September 2007 | url-access = subscription }}</ref>

ATP synthase releases this stored energy by completing the circuit and allowing protons to flow down the electrochemical gradient, back to the N-side of the membrane.<ref name=Schultz>{{cite journal | vauthors = Schultz BE, Chan SI | title = Structures and proton-pumping strategies of mitochondrial respiratory enzymes | journal = Annual Review of Biophysics and Biomolecular Structure | volume = 30 | pages = 23–65 | year = 2001 | pmid = 11340051 | doi = 10.1146/annurev.biophys.30.1.23 | url = https://resolver.caltech.edu/CaltechAUTHORS:SCHarbbs01 | author-link2 = Sunney Chan }}</ref> The electrochemical gradient drives the rotation of part of the enzyme's structure and couples this motion to the synthesis of ATP.

The two components of the proton-motive force are [[thermodynamic]]ally equivalent: In mitochondria, the largest part of energy is provided by the potential; in [[alkaliphile]] bacteria the electrical energy even has to compensate for a counteracting inverse pH difference. Inversely, [[chloroplast]]s operate mainly on ΔpH. However, they also require a small membrane potential for the kinetics of ATP synthesis. In the case of the [[Fusobacteriota|fusobacterium]] ''[[Propionigenium modestum]]'' it drives the counter-rotation of subunits a and c of the F<sub>O</sub> motor of ATP synthase.<ref name=Dimroth2000 />

The amount of energy released by oxidative phosphorylation is high, compared with the amount produced by [[fermentation]]. [[Glycolysis]] produces only 2 ATP molecules, but somewhere between 30 and 36 ATPs are produced by the oxidative phosphorylation of the 10 NADH and 2 succinate molecules made by converting one molecule of [[glucose]] to carbon dioxide and water,<ref>{{cite journal | vauthors = Rich PR | title = The molecular machinery of Keilin's respiratory chain | journal = Biochemical Society Transactions | volume = 31 | issue = Pt 6 | pages = 1095–1105 | date = December 2003 | pmid = 14641005 | doi = 10.1042/bst0311095 }}</ref> while each cycle of [[beta oxidation]] of a [[fatty acid]] yields about 14 ATPs. These ATP yields are theoretical maximum values; in practice, some protons leak across the membrane, lowering the yield of ATP.<ref>{{cite journal | vauthors = Porter RK, Brand MD | title = Mitochondrial proton conductance and H+/O ratio are independent of electron transport rate in isolated hepatocytes | journal = The Biochemical Journal | volume = 310 | issue = Pt 2 | pages = 379–382 | date = September 1995 | pmid = 7654171 | pmc = 1135905 | doi = 10.1042/bj3100379 }}</ref>

== Electron and proton transfer molecules ==
{{further|Coenzyme|Cofactor (biochemistry)}}
[[File:Ubiquinone–ubiquinol conversion.svg|thumb|250px|left|Reduction of [[coenzyme Q]] from its [[ubiquinone]] form (Q) to the reduced ubiquinol form (QH<sub>2</sub>).]]
The electron transport chain carries both protons and electrons, passing electrons from donors to acceptors, and transporting protons across a membrane. These processes use both soluble and protein-bound transfer molecules. In the mitochondria, electrons are transferred within the intermembrane space by the water-[[soluble]] electron transfer protein [[cytochrome c]].<ref>{{cite journal | vauthors = Mathews FS | title = The structure, function and evolution of cytochromes | journal = Progress in Biophysics and Molecular Biology | volume = 45 | issue = 1 | pages = 1–56 | year = 1985 | pmid = 3881803 | doi = 10.1016/0079-6107(85)90004-5 | doi-access = free }}</ref> This carries only electrons, and these are transferred by the reduction and oxidation of an [[iron]] atom that the protein holds within a [[heme]] group in its structure. Cytochrome c is also found in some bacteria, where it is located within the [[periplasmic space]].<ref>{{cite journal | vauthors = Wood PM | title = Why do c-type cytochromes exist? | journal = FEBS Letters | volume = 164 | issue = 2 | pages = 223–226 | date = December 1983 | pmid = 6317447 | doi = 10.1016/0014-5793(83)80289-0 | s2cid = 7685958 | doi-access = free | bibcode = 1983FEBSL.164..223W }}</ref>

Within the inner mitochondrial membrane, the [[lipid]]-soluble electron carrier [[coenzyme Q10]] (Q) carries both electrons and protons by a [[redox]] cycle.<ref>{{cite journal | vauthors = Crane FL | title = Biochemical functions of coenzyme Q10 | journal = Journal of the American College of Nutrition | volume = 20 | issue = 6 | pages = 591–598 | date = December 2001 | pmid = 11771674 | doi = 10.1080/07315724.2001.10719063 | s2cid = 28013583 }}</ref> This small [[1,4-Benzoquinone|benzoquinone]] molecule is very [[hydrophobe|hydrophobic]], so it diffuses freely within the membrane. When Q accepts two electrons and two protons, it becomes reduced to the ''[[Hydroquinone|ubiquinol]]'' form (QH<sub>2</sub>); when QH<sub>2</sub> releases two electrons and two protons, it becomes oxidized back to the ''ubiquinone'' (Q) form. As a result, if two enzymes are arranged so that Q is reduced on one side of the membrane and QH<sub>2</sub> oxidized on the other, ubiquinone will couple these reactions and shuttle protons across the membrane.<ref>{{cite journal | vauthors = Mitchell P | title = Keilin's respiratory chain concept and its chemiosmotic consequences | journal = Science | volume = 206 | issue = 4423 | pages = 1148–1159 | date = December 1979 | pmid = 388618 | doi = 10.1126/science.388618 | bibcode = 1979Sci...206.1148M }}</ref> Some bacterial electron transport chains use different quinones, such as [[vitamin K|menaquinone]], in addition to ubiquinone.<ref name="Søballe">{{cite journal | vauthors = Søballe B, Poole RK | title = Microbial ubiquinones: multiple roles in respiration, gene regulation and oxidative stress management | journal = Microbiology | volume = 145 | issue = 8 | pages = 1817–1830 | date = August 1999 | pmid = 10463148 | doi = 10.1099/13500872-145-8-1817 | url = http://mic.sgmjournals.org/cgi/reprint/145/8/1817.pdf | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20080529070520/http://mic.sgmjournals.org/cgi/reprint/145/8/1817.pdf | archive-date = 2008-05-29 }}</ref>

Within proteins, electrons are transferred between [[Flavin group|flavin]] cofactors,<ref name=Schultz/><ref name=Johnson>{{cite journal | vauthors = Johnson DC, Dean DR, Smith AD, Johnson MK | title = Structure, function, and formation of biological iron-sulfur clusters | journal = Annual Review of Biochemistry | volume = 74 | pages = 247–281 | year = 2005 | pmid = 15952888 | doi = 10.1146/annurev.biochem.74.082803.133518 }}</ref> [[iron–sulfur cluster]]s and cytochromes. There are several types of iron–sulfur cluster. The simplest kind found in the electron transfer chain consists of two iron atoms joined by two atoms of inorganic [[sulfur]]; these are called [2Fe–2S] clusters. The second kind, called [4Fe–4S], contains a cube of four iron atoms and four sulfur atoms. Each iron atom in these clusters is coordinated by an additional [[amino acid]], usually by the sulfur atom of [[cysteine]]. Metal ion cofactors undergo redox reactions without binding or releasing protons, so in the electron transport chain they serve solely to transport electrons through proteins. Electrons move quite long distances through proteins by hopping along chains of these cofactors.<ref>{{cite journal | vauthors = Page CC, Moser CC, Chen X, Dutton PL | title = Natural engineering principles of electron tunnelling in biological oxidation-reduction | journal = Nature | volume = 402 | issue = 6757 | pages = 47–52 | date = November 1999 | pmid = 10573417 | doi = 10.1038/46972 | s2cid = 4431405 | bibcode = 1999Natur.402...47P }}</ref> This occurs by [[quantum tunnelling]], which is rapid over distances of less than 1.4{{e|−9}} m.<ref>{{cite journal | vauthors = Leys D, Scrutton NS | title = Electrical circuitry in biology: emerging principles from protein structure | journal = Current Opinion in Structural Biology | volume = 14 | issue = 6 | pages = 642–647 | date = December 2004 | pmid = 15582386 | doi = 10.1016/j.sbi.2004.10.002 }}</ref>

== 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 | hdl = 11370/de48e914-ff0e-4707-8325-0f63ca48a67c | hdl-access = free }}</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:NADH Dehydrogenase Mechanism.pdf|350px|thumb|right|Complex I or [[NADH dehydrogenase|NADH-Q oxidoreductase]]. The abbreviations are discussed in the text.]]

[[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 {{val|1000|ul=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 | hdl = 11370/7eb43dde-007b-4ba7-887b-bb4e29d6088b | hdl-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>

== Prokaryotic electron transport chains ==
{{further|Microbial metabolism}}
In contrast to the general similarity in structure and function of the electron transport chains in eukaryotes, [[bacteria]] and [[archaea]] possess a large variety of electron-transfer enzymes. These use an equally wide set of chemicals as substrates.<ref>{{cite journal | vauthors = Nealson KH | title = Post-Viking microbiology: new approaches, new data, new insights | journal = Origins of Life and Evolution of the Biosphere | volume = 29 | issue = 1 | pages = 73–93 | date = January 1999 | pmid = 11536899 | doi = 10.1023/A:1006515817767 | s2cid = 12289639 | bibcode = 1999OLEB...29...73N }}</ref> In common with eukaryotes, prokaryotic electron transport uses the energy released from the oxidation of a substrate to pump ions across a membrane and generate an electrochemical gradient. For bacteria, oxidative phosphorylation is understood in most detail in ''[[Escherichia coli]]'', while archaeal systems are, at present, poorly understood.<ref>{{cite journal | vauthors = Schäfer G, Engelhard M, Müller V | title = Bioenergetics of the Archaea | journal = Microbiology and Molecular Biology Reviews | volume = 63 | issue = 3 | pages = 570–620 | date = September 1999 | pmid = 10477309 | pmc = 103747 | doi = 10.1128/MMBR.63.3.570-620.1999 }}</ref>

The main difference between eukaryotic and prokaryotic oxidative phosphorylation is that bacteria and archaea use many different substances to donate or accept electrons. This allows prokaryotes to grow under a wide variety of environmental conditions.<ref name=Ingledew>{{cite journal | vauthors = Ingledew WJ, Poole RK | title = The respiratory chains of Escherichia coli | journal = Microbiological Reviews | volume = 48 | issue = 3 | pages = 222–271 | date = September 1984 | pmid = 6387427 | pmc = 373010 | doi = 10.1128/mmbr.48.3.222-271.1984 }}</ref> In ''E. coli'', for example, oxidative phosphorylation can be driven by a large number of pairs of reducing agents and oxidizing agents, which are listed below. The [[Standard electrode potential#Non-standard condition|midpoint potential]] of a chemical measures how much energy is released when it is oxidized or reduced, with reducing agents having negative potentials and oxidizing agents positive potentials.

{| class="wikitable sortable" style="margin-left: auto; margin-right: auto;"
|+ Respiratory enzymes and substrates in ''E. coli''.<ref name=Unden>{{cite journal | vauthors = Unden G, Bongaerts J | title = Alternative respiratory pathways of Escherichia coli: energetics and transcriptional regulation in response to electron acceptors | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1320 | issue = 3 | pages = 217–234 | date = July 1997 | pmid = 9230919 | doi = 10.1016/S0005-2728(97)00034-0 | doi-access = free }}</ref>
|-
!Respiratory enzyme
![[redox|Redox pair]]
! [[Standard electrode potential#Non-standard condition|Midpoint potential]]&nbsp;
(Volts)
|-
| [[Ubiquinol oxidase]]
| [[Oxygen]] / [[Water]]
| align="center" | +0.82
|-
| [[Nitrate reductase]]
| [[Nitrate]] / [[Nitrite]]
| align="center" | +0.42
|-
| [[Nitrite reductase]]
| [[Nitrite]] / [[Ammonia]]
| align="center" | +0.36
|-
| [[DMSO reductase|Dimethyl sulfoxide reductase]]
| [[dimethyl sulfoxide|DMSO]] / [[Dimethyl sulfide|DMS]]
| align="center" | +0.16
|-
| [[Trimethylamine N-oxide reductase|Trimethylamine ''N''-oxide reductase]]
| [[Trimethylamine N-oxide|TMAO]] / [[Trimethylamine|TMA]]
| align="center" | +0.13
|-
| [[Fumarate reductase]]
| [[Fumaric acid|Fumarate]] / [[Succinic acid|Succinate]]
| align="center" | +0.03
|-
| [[Succinate - coenzyme Q reductase|Succinate dehydrogenase]]
| [[Fumaric acid|Fumarate]] / [[Succinic acid|Succinate]]
| align="center" | +0.03
|-
| [[Quinoprotein glucose dehydrogenase|Glucose dehydrogenase]]
| [[gluconic acid|Gluconate]] / [[Glucose]]
| align="center" | −0.14
|-
| [[Glycerol-3-phosphate dehydrogenase]]
| [[dihydroxyacetone phosphate|DHAP]] / [[Glycerol 3-phosphate|Gly-3-P]]
| align="center" | −0.19
|-
| [[Lactate dehydrogenase]]
| [[pyruvic acid|Pyruvate]] / [[Lactic acid|Lactate]]
| align="center" | −0.19
|-
| [[NADH dehydrogenase]]
| [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]] / [[Nicotinamide adenine dinucleotide|NADH]]
| align="center" | −0.32
|-
| [[Hydrogenase]]
| [[Proton]] / [[Hydrogen]]
| align="center" | −0.42
|-
| [[Formate dehydrogenase]]
| [[Bicarbonate]] / [[Formate]]
| align=center | −0.43
|-
| [[D-amino acid dehydrogenase|<small>D</small>-amino acid dehydrogenase]]
|  [[Oxoacid|2-oxoacid]] + [[ammonia]] / [[Amino acid|<small>D</small>-amino acid]]
| align=center | ?
|-
| [[Pyruvate dehydrogenase#Related enzymes|Pyruvate oxidase]]
|  [[acetic acid|Acetate]] + [[Carbon dioxide]] / [[pyruvic acid|Pyruvate]]
| align="center" | ?
|}

As shown above, ''E. coli'' can grow with reducing agents such as formate, hydrogen, or lactate as electron donors, and nitrate, DMSO, or oxygen as acceptors.<ref name=Ingledew/> The larger the difference in midpoint potential between an oxidizing and reducing agent, the more energy is released when they react. Out of these compounds, the succinate/fumarate pair is unusual, as its midpoint potential is close to zero. Succinate can therefore be oxidized to fumarate if a strong oxidizing agent such as oxygen is available, or fumarate can be reduced to succinate using a strong reducing agent such as formate. These alternative reactions are catalyzed by [[Succinate - coenzyme Q reductase|succinate dehydrogenase]] and [[fumarate reductase]], respectively.<ref>{{cite journal | vauthors = Cecchini G, Schröder I, Gunsalus RP, Maklashina E | title = Succinate dehydrogenase and fumarate reductase from Escherichia coli | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1553 | issue = 1–2 | pages = 140–157 | date = January 2002 | pmid = 11803023 | doi = 10.1016/S0005-2728(01)00238-9 | doi-access = free }}</ref>

Some prokaryotes use redox pairs that have only a small difference in midpoint potential. For example, [[nitrification|nitrifying]] bacteria such as ''[[Nitrobacter]]'' oxidize nitrite to nitrate, donating the electrons to oxygen. The small amount of energy released in this reaction is enough to pump protons and generate ATP, but not enough to produce NADH or NADPH directly for use in [[anabolism]].<ref>{{cite journal | vauthors = Freitag A, Bock E |year=1990 |title=Energy conservation in Nitrobacter |journal=FEMS Microbiology Letters |volume=66 |issue=1–3 |pages=157–62 |doi=10.1111/j.1574-6968.1990.tb03989.x |doi-access=free }}</ref> This problem is solved by using a [[nitrite oxidoreductase]] to produce enough proton-motive force to run part of the electron transport chain in reverse, causing complex I to generate NADH.<ref>{{cite journal | vauthors = Starkenburg SR, Chain PS, Sayavedra-Soto LA, Hauser L, Land ML, Larimer FW, Malfatti SA, Klotz MG, Bottomley PJ, Arp DJ, Hickey WJ | title = Genome sequence of the chemolithoautotrophic nitrite-oxidizing bacterium Nitrobacter winogradskyi Nb-255 | journal = Applied and Environmental Microbiology | volume = 72 | issue = 3 | pages = 2050–2063 | date = March 2006 | pmid = 16517654 | pmc = 1393235 | doi = 10.1128/AEM.72.3.2050-2063.2006 | bibcode = 2006ApEnM..72.2050S }}</ref><ref>{{cite journal | vauthors = Yamanaka T, Fukumori Y | title = The nitrite oxidizing system of Nitrobacter winogradskyi | journal = FEMS Microbiology Reviews | volume = 54 | issue = 4 | pages = 259–270 | date = December 1988 | pmid = 2856189 | doi = 10.1111/j.1574-6968.1988.tb02746.x | doi-access = free }}</ref>

Prokaryotes control their use of these electron donors and acceptors by varying which enzymes are produced in response to environmental conditions.<ref>{{cite journal | vauthors = Iuchi S, Lin EC | title = Adaptation of Escherichia coli to redox environments by gene expression | journal = Molecular Microbiology | volume = 9 | issue = 1 | pages = 9–15 | date = July 1993 | pmid = 8412675 | doi = 10.1111/j.1365-2958.1993.tb01664.x | s2cid = 39165641 }}</ref> This flexibility is possible because different oxidases and reductases use the same ubiquinone pool. This allows many combinations of enzymes to function together, linked by the common ubiquinol intermediate.<ref name=Unden/> These respiratory chains therefore have a [[modular design]], with easily interchangeable sets of enzyme systems.

In addition to this metabolic diversity, prokaryotes also possess a range of [[isozyme]]s&nbsp;– different enzymes that catalyze the same reaction. For example, in ''E. coli'', there are two different types of ubiquinol oxidase using oxygen as an electron acceptor. Under highly aerobic conditions, the cell uses an oxidase with a low affinity for oxygen that can transport two protons per electron. However, if levels of oxygen fall, they switch to an oxidase that transfers only one proton per electron, but has a high affinity for oxygen.<ref>{{cite journal | vauthors = Calhoun MW, Oden KL, Gennis RB, de Mattos MJ, Neijssel OM | title = Energetic efficiency of Escherichia coli: effects of mutations in components of the aerobic respiratory chain | journal = Journal of Bacteriology | volume = 175 | issue = 10 | pages = 3020–3025 | date = May 1993 | pmid = 8491720 | pmc = 204621 | doi = 10.1128/jb.175.10.3020-3025.1993 | url = http://jb.asm.org/cgi/reprint/175/10/3020.pdf | url-status = live | archive-url = https://web.archive.org/web/20070927135240/http://jb.asm.org/cgi/reprint/175/10/3020.pdf | archive-date = 2007-09-27 }}</ref>

== ATP synthase (complex V) ==
{{further|ATP synthase}}

ATP synthase, also called ''complex V'', is the final enzyme in the oxidative phosphorylation pathway. This enzyme is found in all forms of life and functions in the same way in both prokaryotes and eukaryotes.<ref name=Boyer>{{cite journal | vauthors = Boyer PD | title = The ATP synthase--a splendid molecular machine | journal = Annual Review of Biochemistry | volume = 66 | pages = 717–749 | year = 1997 | pmid = 9242922 | doi = 10.1146/annurev.biochem.66.1.717 }}</ref> The enzyme uses the energy stored in a proton gradient across a membrane to drive the synthesis of ATP from ADP and [[phosphate]] (P<sub>i</sub>). Estimates of the number of protons required to synthesize one ATP have ranged from three to four,<ref>{{cite journal | vauthors = Van Walraven HS, Strotmann H, Schwarz O, Rumberg B | title = The H+/ATP coupling ratio of the ATP synthase from thiol-modulated chloroplasts and two cyanobacterial strains is four | journal = FEBS Letters | volume = 379 | issue = 3 | pages = 309–313 | date = February 1996 | pmid = 8603713 | doi = 10.1016/0014-5793(95)01536-1 | bibcode = 1996FEBSL.379..309V | s2cid = 35989618 }}</ref><ref>{{cite journal | vauthors = Yoshida M, Muneyuki E, Hisabori T | title = ATP synthase--a marvellous rotary engine of the cell | journal = Nature Reviews. Molecular Cell Biology | volume = 2 | issue = 9 | pages = 669–677 | date = September 2001 | pmid = 11533724 | doi = 10.1038/35089509 | s2cid = 3926411 }}</ref> with some suggesting cells can vary this ratio, to suit different conditions.<ref>{{cite journal | vauthors = Schemidt RA, Qu J, Williams JR, Brusilow WS | title = Effects of carbon source on expression of F0 genes and on the stoichiometry of the c subunit in the F1F0 ATPase of Escherichia coli | journal = Journal of Bacteriology | volume = 180 | issue = 12 | pages = 3205–3208 | date = June 1998 | pmid = 9620972 | pmc = 107823 | doi = 10.1128/jb.180.12.3205-3208.1998 }}</ref>

{{NumBlk|:|<chem>ADP + P_i + 4H+_{intermembrane} <=> ATP + H2O + 4H+_{matrix}</chem>|{{EquationRef|6}}}}

This [[phosphorylation]] reaction is an [[chemical equilibrium|equilibrium]], which can be shifted by altering the proton-motive force. In the absence of a proton-motive force, the ATP synthase reaction will run from right to left, hydrolyzing ATP and pumping protons out of the matrix across the membrane. However, when the proton-motive force is high, the reaction is forced to run in the opposite direction; it proceeds from left to right, allowing protons to flow down their concentration gradient and turning ADP into ATP.<ref name=Boyer/> Indeed, in the closely related [[V-ATPase|vacuolar type H+-ATPases]], the hydrolysis reaction is used to acidify cellular compartments, by pumping protons and hydrolysing ATP.<ref>{{cite journal | vauthors = Nelson N, Perzov N, Cohen A, Hagai K, Padler V, Nelson H | title = The cellular biology of proton-motive force generation by V-ATPases | journal = The Journal of Experimental Biology | volume = 203 | issue = Pt 1 | pages = 89–95 | date = January 2000 | pmid = 10600677 | doi = 10.1242/jeb.203.1.89 | bibcode = 2000JExpB.203...89N | url = http://jeb.biologists.org/cgi/reprint/203/1/89 | url-status = live | archive-url = https://web.archive.org/web/20070930043711/http://jeb.biologists.org/cgi/reprint/203/1/89 | archive-date = 30 September 2007 | url-access = subscription }}</ref>

ATP synthase is a massive protein complex with a mushroom-like shape. The mammalian enzyme complex contains 16 subunits and has a mass of approximately 600 [[kilodalton]]s.<ref>{{cite journal | vauthors = Rubinstein JL, Walker JE, Henderson R | title = Structure of the mitochondrial ATP synthase by electron cryomicroscopy | journal = The EMBO Journal | volume = 22 | issue = 23 | pages = 6182–6192 | date = December 2003 | pmid = 14633978 | pmc = 291849 | doi = 10.1093/emboj/cdg608 }}</ref> The portion embedded within the membrane is called F<sub>O</sub> and contains a ring of c subunits and the proton channel. The stalk and the ball-shaped headpiece is called F<sub>1</sub> and is the site of ATP synthesis. The ball-shaped complex at the end of the F<sub>1</sub> portion contains six proteins of two different kinds (three α subunits and three β subunits), whereas the "stalk" consists of one protein: the γ subunit, with the tip of the stalk extending into the ball of α and β subunits.<ref>{{cite journal | vauthors = Leslie AG, Walker JE | title = Structural model of F1-ATPase and the implications for rotary catalysis | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 355 | issue = 1396 | pages = 465–471 | date = April 2000 | pmid = 10836500 | pmc = 1692760 | doi = 10.1098/rstb.2000.0588 }}</ref> Both the α and β subunits bind nucleotides, but only the β subunits catalyze the ATP synthesis reaction. Reaching along the side of the F<sub>1</sub> portion and back into the membrane is a long rod-like subunit that anchors the α and β subunits into the base of the enzyme.

As protons cross the membrane through the channel in the base of ATP synthase, the F<sub>O</sub> proton-driven motor rotates.<ref>{{cite journal | vauthors = Noji H, Yoshida M | title = The rotary machine in the cell, ATP synthase | journal = The Journal of Biological Chemistry | volume = 276 | issue = 3 | pages = 1665–1668 | date = January 2001 | pmid = 11080505 | doi = 10.1074/jbc.R000021200 | s2cid = 30953216 | doi-access = free }}</ref> Rotation might be caused by changes in the [[ionization]] of amino acids in the ring of c subunits causing [[electrostatic]] interactions that propel the ring of c subunits past the proton channel.<ref>{{cite journal | vauthors = Capaldi RA, Aggeler R | title = Mechanism of the F(1)F(0)-type ATP synthase, a biological rotary motor | journal = Trends in Biochemical Sciences | volume = 27 | issue = 3 | pages = 154–160 | date = March 2002 | pmid = 11893513 | doi = 10.1016/S0968-0004(01)02051-5 }}<!--PubMed listing does use incorrect "F0" notation--></ref> This rotating ring in turn drives the rotation of the central [[axle]] (the γ subunit stalk) within the α and β subunits. The α and β subunits are prevented from rotating themselves by the side-arm, which acts as a [[stator]]. This movement of the tip of the γ subunit within the ball of α and β subunits provides the energy for the active sites in the β subunits to undergo a cycle of movements that produces and then releases ATP.<ref name=Dimroth2006>{{cite journal | vauthors = Dimroth P, von Ballmoos C, Meier T | title = Catalytic and mechanical cycles in F-ATP synthases. Fourth in the Cycles Review Series | journal = EMBO Reports | volume = 7 | issue = 3 | pages = 276–282 | date = March 2006 | pmid = 16607397 | pmc = 1456893 | doi = 10.1038/sj.embor.7400646 }}</ref>
[[File:ATPsyn.gif|thumb|220px|right|Mechanism of [[ATP synthase]]. ATP is shown in red, ADP and phosphate in pink and the rotating γ subunit in black.]]
This ATP synthesis reaction is called the ''binding change mechanism'' and involves the active site of a β subunit cycling between three states.<ref name=Gresser>{{cite journal | vauthors = Gresser MJ, Myers JA, Boyer PD | title = Catalytic site cooperativity of beef heart mitochondrial F1 adenosine triphosphatase. Correlations of initial velocity, bound intermediate, and oxygen exchange measurements with an alternating three-site model | journal = The Journal of Biological Chemistry | volume = 257 | issue = 20 | pages = 12030–12038 | date = October 1982 | pmid = 6214554 | doi = 10.1016/S0021-9258(18)33672-X | url = http://www.jbc.org/cgi/reprint/257/20/12030 | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20070929103100/http://www.jbc.org/cgi/reprint/257/20/12030 | archive-date = 29 September 2007 }}</ref> In the "open" state, ADP and phosphate enter the active site (shown in brown in the diagram). The protein then closes up around the molecules and binds them loosely&nbsp;– the "loose" state (shown in red). The enzyme then changes shape again and forces these molecules together, with the active site in the resulting "tight" state (shown in pink) binding the newly produced ATP molecule with very high [[Dissociation constant|affinity]]. Finally, the active site cycles back to the open state, releasing ATP and binding more ADP and phosphate, ready for the next cycle.

In some bacteria and archaea, ATP synthesis is driven by the movement of sodium ions through the cell membrane, rather than the movement of protons.<ref>{{cite journal | vauthors = Dimroth P | title = Bacterial sodium ion-coupled energetics | journal = Antonie van Leeuwenhoek | volume = 65 | issue = 4 | pages = 381–395 | year = 1994 | pmid = 7832594 | doi = 10.1007/BF00872221 | s2cid = 23763996 }}</ref><ref name=Becher>{{cite journal | vauthors = Becher B, Müller V | title = Delta mu Na+ drives the synthesis of ATP via an delta mu Na(+)-translocating F1F0-ATP synthase in membrane vesicles of the archaeon Methanosarcina mazei Gö1 | journal = Journal of Bacteriology | volume = 176 | issue = 9 | pages = 2543–2550 | date = May 1994 | pmid = 8169202 | pmc = 205391 | doi = 10.1128/jb.176.9.2543-2550.1994 }}</ref> Archaea such as ''[[Methanococcus]]'' also contain the A<sub>1</sub>A<sub>o</sub> synthase, a form of the enzyme that contains additional proteins with little similarity in sequence to other bacterial and eukaryotic ATP synthase subunits. It is possible that, in some species, the A<sub>1</sub>A<sub>o</sub> form of the enzyme is a specialized sodium-driven ATP synthase,<ref>{{cite journal | vauthors = Müller V | title = An exceptional variability in the motor of archael A1A0 ATPases: from multimeric to monomeric rotors comprising 6-13 ion binding sites | journal = Journal of Bioenergetics and Biomembranes | volume = 36 | issue = 1 | pages = 115–125 | date = February 2004 | pmid = 15168615 | doi = 10.1023/B:JOBB.0000019603.68282.04 | s2cid = 24887884 }}</ref> but this might not be true in all cases.<ref name=Becher/>

== Reactive oxygen species ==
{{further|Oxidative stress|Antioxidant}}
Molecular oxygen is a good terminal [[electron acceptor]] because it is a strong oxidizing agent. The reduction of oxygen does involve potentially harmful intermediates.<ref name=Davies>{{cite journal | vauthors = Davies KJ | title = Oxidative stress: the paradox of aerobic life | journal = Biochemical Society Symposium | volume = 61 | pages = 1–31 | year = 1995 | pmid = 8660387 | doi = 10.1042/bss0610001 }}</ref> Although the transfer of four electrons and four protons reduces oxygen to water, which is harmless, transfer of one or two electrons produces [[superoxide]] or [[peroxide]] anions, which are dangerously reactive.

{{NumBlk|:|<chem>O2 ->[\ce{e^-}] \underset{Superoxide}{O2^{\underline{\bullet}}} ->[\ce{e^-}] \underset{Peroxide}{O2^{2-}}</chem>|{{EquationRef|7}}}}

These [[reactive oxygen species]] and their reaction products, such as the [[hydroxyl]] radical, are very harmful to cells, as they oxidize proteins and cause [[mutation]]s in [[DNA]]. This cellular damage may contribute to [[disease]] and is proposed as one cause of [[free-radical theory of aging|aging]].<ref>{{cite journal | vauthors = Rattan SI | title = Theories of biological aging: genes, proteins, and free radicals | journal = Free Radical Research | volume = 40 | issue = 12 | pages = 1230–1238 | date = December 2006 | pmid = 17090411 | doi = 10.1080/10715760600911303 | url = http://www.link-age.eu/Freeradicalresearch-Rattan.pdf | access-date = 2017-10-27 | s2cid = 11125090 | citeseerx = 10.1.1.476.9259 | archive-url = https://web.archive.org/web/20140614080412/http://www.link-age.eu/Freeradicalresearch-Rattan.pdf | archive-date = 2014-06-14 }}</ref><ref>{{cite journal | vauthors = Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J | title = Free radicals and antioxidants in normal physiological functions and human disease | journal = The International Journal of Biochemistry & Cell Biology | volume = 39 | issue = 1 | pages = 44–84 | year = 2007 | pmid = 16978905 | doi = 10.1016/j.biocel.2006.07.001 }}</ref>

The cytochrome c oxidase complex is highly efficient at reducing oxygen to water, and it releases very few partly reduced intermediates; however small amounts of superoxide anion and peroxide are produced by the electron transport chain.<ref name=Raha>{{cite journal | vauthors = Raha S, Robinson BH | title = Mitochondria, oxygen free radicals, disease and ageing | journal = Trends in Biochemical Sciences | volume = 25 | issue = 10 | pages = 502–508 | date = October 2000 | pmid = 11050436 | doi = 10.1016/S0968-0004(00)01674-1 }}</ref> Particularly important is the reduction of [[coenzyme Q]] in complex III, as a highly reactive ubisemiquinone free radical is formed as an intermediate in the Q cycle. This unstable species can lead to electron "leakage" when electrons transfer directly to oxygen, forming superoxide.<ref>{{cite journal | vauthors = Finkel T, Holbrook NJ | title = Oxidants, oxidative stress and the biology of ageing | journal = Nature | volume = 408 | issue = 6809 | pages = 239–247 | date = November 2000 | pmid = 11089981 | doi = 10.1038/35041687 | s2cid = 2502238 | bibcode = 2000Natur.408..239F }}</ref> As the production of reactive oxygen species by these proton-pumping complexes is greatest at high membrane potentials, it has been proposed that mitochondria regulate their activity to maintain the membrane potential within a narrow range that balances ATP production against oxidant generation.<ref>{{cite journal | vauthors = Kadenbach B, Ramzan R, Wen L, Vogt S | title = New extension of the Mitchell Theory for oxidative phosphorylation in mitochondria of living organisms | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1800 | issue = 3 | pages = 205–212 | date = March 2010 | pmid = 19409964 | doi = 10.1016/j.bbagen.2009.04.019 }}</ref> For instance, oxidants can activate [[uncoupling protein]]s that reduce membrane potential.<ref>{{cite journal | vauthors = Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA, Harper JA, Roebuck SJ, Morrison A, Pickering S, Clapham JC, Brand MD | title = Superoxide activates mitochondrial uncoupling proteins | journal = Nature | volume = 415 | issue = 6867 | pages = 96–99 | date = January 2002 | pmid = 11780125 | doi = 10.1038/415096a | s2cid = 4349744 | bibcode = 2002Natur.415...96E }}</ref>

To counteract these reactive oxygen species, cells contain numerous [[antioxidant]] systems, including antioxidant [[vitamin]]s such as [[vitamin C]] and [[vitamin E]], and antioxidant enzymes such as [[superoxide dismutase]], [[catalase]], and [[peroxidases]],<ref name=Davies/> which detoxify the reactive species, limiting damage to the cell.

== In hypoxic/anoxic conditions ==
As [[oxygen]] is fundamental for oxidative phosphorylation, a shortage in O<sub>2</sub> level can alter ATP production rates. The proton motive force and ATP production can be maintained by intracellular acidosis.<ref>{{cite journal | vauthors = Devaux JB, Hedges CP, Birch N, Herbert N, Renshaw GM, Hickey AJ | title = Acidosis Maintains the Function of Brain Mitochondria in Hypoxia-Tolerant Triplefin Fish: A Strategy to Survive Acute Hypoxic Exposure? | journal = Frontiers in Physiology | volume = 9 | page = 1941 | date = January 2019 | pmid = 30713504 | pmc = 6346031 | doi = 10.3389/fphys.2018.01941 | doi-access = free }}</ref> Cytosolic protons that have accumulated with ATP hydrolysis and [[lactic acidosis]] can freely diffuse across the mitochondrial outer-membrane and acidify the inter-membrane space, hence directly contributing to the proton motive force and ATP production.

When exposed to [[Hypoxia (medicine)|hypoxia]]/anoxia (no oxygen), most animals will see damage done to their mitochondria.<ref name="Lesnefsky_2017">{{cite journal | vauthors = Lesnefsky EJ, Chen Q, Tandler B, Hoppel CL | title = Mitochondrial Dysfunction and Myocardial Ischemia-Reperfusion: Implications for Novel Therapies | journal = Annual Review of Pharmacology and Toxicology | volume = 57 | pages = 535–565 | date = January 2017 | pmid = 27860548 | pmc = 11060135 | doi = 10.1146/annurev-pharmtox-010715-103335 }}</ref> From some species, these conditions can happen due to environmental variables, such as low tides,<ref name="Hickey_2012">{{cite journal | vauthors = Hickey AJ, Renshaw GM, Speers-Roesch B, Richards JG, Wang Y, Farrell AP, Brauner CJ | title = A radical approach to beating hypoxia: depressed free radical release from heart fibres of the hypoxia-tolerant epaulette shark (Hemiscyllum ocellatum) | journal = Journal of Comparative Physiology B | volume = 182 | issue = 1 | pages = 91–100 | date = January 2012 | pmid = 21748398 | doi = 10.1007/s00360-011-0599-6 }}</ref> low temperatures,<ref name="Hawrysh_2022">{{cite journal | vauthors = Hawrysh PJ, Myrka AM, Buck LT | title = Review: A history and perspective of mitochondria in the context of anoxia tolerance | journal = Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology | volume = 260 | article-number = 110733 | date = 2022 | pmid = 35288242 | doi = 10.1016/j.cbpb.2022.110733 }}</ref> or general living conditions, like living in a hypoxic underground burrow.<ref name="Pamenter_2018">{{cite journal | vauthors = Pamenter ME, Lau GY, Richards JG, Milsom WK | title = Naked mole rat brain mitochondria electron transport system flux and H<sup>+</sup> leak are reduced during acute hypoxia | journal = The Journal of Experimental Biology | volume = 221 | issue = Pt 4 | pages = jeb171397 | date = February 2018 | pmid = 29361591 | doi = 10.1242/jeb.171397 }}</ref> In humans, these conditions are commonly met in medical emergencies such as [[stroke]]s, [[ischemia]], and [[asphyxia]].

Despite this, or perhaps due to it, some species have developed their own defense mechanisms against anoxia/hypoxia, as well as during [[Reperfusion therapy|reperfusion]]/reoxygenation. These mechanisms are diverse and differ between [[endotherm]]s and [[ectotherm]]s and can differ even at the species level.

=== Endotherms ===

==== Hypoxia/anoxia intolerance ====
Most mammals and birds are intolerant to low/no oxygen conditions. For the heart, in the absence of oxygen, the first four [[Electron transport chain|complexes]] of the electron transport chain decrease in activity.<ref name="Lesnefsky_2017" /> This will lead to protons leaking through the [[inner mitochondrial membrane]] without complexes [[Respiratory complex I|I]], [[Complex III|III]], and [[Complex IV|IV]] pushing protons back through to maintain the proton gradient. There is also electron leak (an event where electrons leak out of the electron transport chain), which happens because [[Nadh dehydrogenase|NADH dehydrogenase]] within Complex I becomes damaged, which allows for the production of ROS ([[reactive oxygen species]]) during ischemia.<ref name="Chen_2007">{{cite journal | vauthors = Chen Q, Camara AK, Stowe DF, Hoppel CL, Lesnefsky EJ | title = Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion | journal = American Journal of Physiology. Cell Physiology | volume = 292 | issue = 1 | pages = C137-C147 | date = January 2007 | pmid = 16971498 | doi = 10.1152/ajpcell.00270.2006 }}</ref> This will lead to the reversing of [[ATP synthase|Complex V]], which forces protons from the [[Mitochondrial matrix|matrix]] back into the [[Intermembrane space|inner membrane space]], against their [[Fick's laws of diffusion|concentration gradient]]. Forcing protons against their concentration gradient requires energy, so Complex V uses up ATP as an energy source.<ref name="St-Pierre_2000">{{cite journal | vauthors = St-Pierre J, Brand MD, Boutilier RG | title = Mitochondria as ATP consumers: cellular treason in anoxia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 15 | pages = 8670–8674 | date = July 2000 | pmid = 10890886 | pmc = 27006 | doi = 10.1073/pnas.140093597 | doi-access = free | bibcode = 2000PNAS...97.8670S }}</ref>

==== Reoxygenation of intolerant animals ====
When oxygen re-enters the system, animals are faced with a different set of problems. Since ATP was used up during the anoxic period, it leads to a lack of [[ADP-ribose diphosphatase|ADP]] within the system.<ref name="Bundgaard_2019">{{cite journal | vauthors = Bundgaard A, James AM, Gruszczyk AV, Martin J, Murphy MP, Fago A | title = Metabolic adaptations during extreme anoxia in the turtle heart and their implications for ischemia-reperfusion injury | journal = Scientific Reports | volume = 9 | issue = 1 | page = 2850 | date = February 2019 | pmid = 30808950 | pmc = 6391391 | doi = 10.1038/s41598-019-39836-5 | bibcode = 2019NatSR...9.2850B }}</ref> This is due to ADP's natural degradation into AMP, resulting in ADP being drained from the system. With no ADP in the system, Complex V is unable to start, meaning the protons will not flow through it to enter the matrix.<ref name="Bundgaard_2019" /> Due to Complex V's reversal during anoxia, the proton gradient has become hyperpolarized (where the proton gradient is highly positively charged). Another factor in this problem is that [[Succinic acid|succinate]] built up during anoxia, so when oxygen is reintroduced, succinate donates electrons to [[Succinate dehydrogenase|Complex II]].<ref name="Bundgaard_2024">{{cite journal | vauthors = Bundgaard A, Borowiec BG, Lau GY | title = Are reactive oxygen species always bad? Lessons from hypoxic ectotherms | journal = The Journal of Experimental Biology | volume = 227 | issue = 6 | pages = jeb246549 | date = March 2024 | pmid = 38533673 | doi = 10.1242/jeb.246549 | bibcode = 2024JExpB.227B6549B }}</ref><ref name="Chouchani_2014">{{cite journal | vauthors = Chouchani ET, Pell VR, Gaude E, Aksentijević D, Sundier SY, Robb EL, Logan A, Nadtochiy SM, Ord EN, Smith AC, Eyassu F, Shirley R, Hu CH, Dare AJ, James AM, Rogatti S, Hartley RC, Eaton S, Costa AS, Brookes PS, Davidson SM, Duchen MR, Saeb-Parsy K, Shattock MJ, Robinson AJ, Work LM, Frezza C, Krieg T, Murphy MP | title = Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS | journal = Nature | volume = 515 | issue = 7527 | pages = 431–435 | date = November 2014 | pmid = 25383517 | pmc = 4255242 | doi = 10.1038/nature13909 | bibcode = 2014Natur.515..431C }}</ref> The hyperpolarized gradient and succinate buildup leads to [[Reverse electron flow|reverse electron transport]], causing [[oxidative stress]],<ref name="Murphy_2009">{{cite journal | vauthors = Murphy MP | title = How mitochondria produce reactive oxygen species | journal = The Biochemical Journal | volume = 417 | issue = 1 | pages = 1–13 | date = January 2009 | pmid = 19061483 | pmc = 2605959 | doi = 10.1042/BJ20081386 }}</ref> which can lead to cellular damage and diseases.<ref name="Bolisetty_2013">{{cite journal | vauthors = Bolisetty S, Jaimes EA | title = Mitochondria and reactive oxygen species: physiology and pathophysiology | journal = International Journal of Molecular Sciences | volume = 14 | issue = 3 | pages = 6306–6344 | date = March 2013 | pmid = 23528859 | pmc = 3634422 | doi = 10.3390/ijms14036306 | doi-access = free }}</ref>

==== Hypoxia/anoxia tolerance ====
The naked mole rat ([[Naked mole-rat|''Heterocephalus glaber'']]) is a hypoxia-tolerant species that sleeps in deep burrows and in large colonies. The depth of these burrows reduces access to oxygen, and sleeping in large groups will deplete the area of oxygen quicker than usual, leading to hypoxia.<ref name="Pamenter_2018" /> The naked mole rat has the unique ability to survive low oxygen conditions for no less than several hours, and zero oxygen conditions for 18 minutes.<ref name="Eaton_2023">{{cite journal | vauthors = Eaton L, Wang T, Roy M, Pamenter ME | title = Naked Mole-Rat Cortex Maintains Reactive Oxygen Species Homeostasis During ''In Vitro'' Hypoxia or Ischemia and Reperfusion | journal = Current Neuropharmacology | volume = 21 | issue = 6 | pages = 1450–1461 | date = 2023 | pmid = 35339183 | pmc = 10324332 | doi = 10.2174/1570159X20666220327220929 }}</ref> One of the ways of combatting hypoxia in the brain is decreasing the reliance on oxygen for ATP production, achieved by decreased respiration rates and proton leak.<ref name="Pamenter_2018" />

==== Reoxygenation of tolerant animals ====
Hypoxia/anoxia tolerant species handle ROS production during reoxygenation better than the intolerant. In the cortex of the naked mole rats, they show better homeostasis of ROS production than intolerant species and seem to lack the burst of ROS that typically comes with reoxygenation.<ref name="Eaton_2023" />

=== Ectotherms ===

==== Hypoxia/anoxia intolerance ====
Research on intolerant ectotherms is more limited than on tolerant ectotherms and intolerant endotherms, but it is shown that anoxia/hypoxia intolerance is different in terms for how long the intolerant survive as opposed to the tolerant between endotherms and ectotherms. While intolerant endotherms only last minutes, intolerant ectotherms can last hours, such as subtidal scallops (''[[Argopecten irradians]]'').<ref name="Ivanina_2016">{{cite journal | vauthors = Ivanina AV, Nesmelova I, Leamy L, Sokolov EP, Sokolova IM | title = Intermittent hypoxia leads to functional reorganization of mitochondria and affects cellular bioenergetics in marine molluscs | journal = The Journal of Experimental Biology | volume = 219 | issue = Pt 11 | pages = 1659–1674 | date = June 2016 | pmid = 27252455 | doi = 10.1242/jeb.134700 | bibcode = 2016JExpB.219.1659I }}</ref> This difference in intolerance could be due to a couple of different factors. One advantage is that the ectothermic inner mitochondrial membrane is less leaky, so less protons will leak through the inner membrane due to differences in the [[Lipid bilayer|phospholipid bilayer]] composition.<ref name="St-Pierre_2000" /> Another advantage ectotherms tend to have in this category is an ability for their mitochondria to properly function in a wide range of temperatures, such as the western fence lizard (''[[Western fence lizard|Sceloporus occidentalis]]).'' While western fence lizards are not considered a hypoxia-tolerant animal, they still showed less temperature sensitivity in their mitochondria than mice mitochondria.<ref name="Berner_1999">{{cite journal | vauthors = Berner NJ | title = Oxygen consumption by mitochondria from an endotherm and an ectotherm | journal = Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology | volume = 124 | issue = 1 | pages = 25–31 | date = September 1999 | pmid = 10582317 | doi = 10.1016/S0305-0491(99)00093-0 }}</ref>

==== Reoxygenation of intolerant animals ====
While it is unclear how reoxygenation affects intolerant ectotherms at the mitochondrial level, there is some research showing how some of them respond. In the hypoxia-sensitive shovelnose ray (''[[Eastern shovelnose ray|Aptychotrema rostrata]]),'' it is shown that ROS production is lower upon reoxygenation compared to rays only exposed to normoxia (normal oxygen levels).<ref name="Hickey_2012" /> This differs from the hypoxia-sensitive endotherm, which would see an increase in ROS production. However, the ray's levels were still higher than the more hypoxia-tolerant Epaulette shark (''[[Epaulette shark|Hemiscyllum ocellatum]]''), which potentially sees hypoxia due to the bouts of low tides that can be seen in reef platforms.<ref name="Hickey_2012" />  Subtidal scallops will see both a decrease in maximal respiration and a depolarization of the membrane during reoxygenation.<ref name="Ivanina_2016" />

==== Hypoxia/anoxia tolerance ====
Hypoxia/Anoxia tolerant ectotherms have shown unique strategies for surviving anoxia. Pond turtles, such as the painted turtle (''[[Painted turtle|Chrysemys picta bellii]]''), will experience anoxia during winter while they overwinter at the bottom of frozen ponds.<ref name="Hawrysh_2022" /> In their cardiac mitochondria, the reversing of Complex V,<ref name="Galli_2013">{{cite journal | vauthors = Galli GL, Lau GY, Richards JG | title = Beating oxygen: chronic anoxia exposure reduces mitochondrial F1FO-ATPase activity in turtle (Trachemys scripta) heart | journal = The Journal of Experimental Biology | volume = 216 | issue = Pt 17 | pages = 3283–3293 | date = September 2013 | pmid = 23926310 | pmc = 4074260 | doi = 10.1242/jeb.087155 | bibcode = 2013JExpB.216.3283G }}</ref>  the usage of ATP, and the build-up of succinate are all prevented during anoxia.<ref name="Bundgaard_2019" /> Crucian carps (''[[Crucian carp|Carassius carassius]]'') also overwinter in frozen ponds and show no loss membrane potential in their cardiac mitochondria during anoxia, but this relies on complexes I and III to be active.<ref name="Scott_2024">{{cite journal | vauthors = Scott MA, Fagernes CE, Nilsson GE, Stensløkken KO | title = Maintained mitochondrial integrity without oxygen in the anoxia-tolerant crucian carp | journal = The Journal of Experimental Biology | volume = 227 | issue = 20 | pages = jeb247409 | date = October 2024 | pmid = 38779846 | pmc = 11418198 | doi = 10.1242/jeb.247409 | bibcode = 2024JExpB.227B7409S }}</ref>

==== Reoxygenation of tolerant animals ====
Pond turtles are able to completely avoid ROS production upon reoxygenation.<ref name="Bundgaard_2023">{{cite journal | vauthors = Bundgaard A, Gruszczyk AV, Prag HA, Williams C, McIntyre A, Ruhr IM, James AM, Galli GL, Murphy MP, Fago A | title = Low production of mitochondrial reactive oxygen species after anoxia and reoxygenation in turtle hearts | journal = The Journal of Experimental Biology | volume = 226 | issue = 9 | pages = jeb245516 | date = May 2023 | pmid = 37066839 | pmc = 10184768 | doi = 10.1242/jeb.245516 | bibcode = 2023JExpB.226B5516B }}</ref> However, crucian carp cannot and are unable to prevent the death of brain cells upon reoxygenation.<ref name="Bundgaard_2020">{{Cite journal | vauthors = Bundgaard A, Ruhr IM, Fago A, Galli GL |date=April 2020 |title=Metabolic adaptations to anoxia and reoxygenation: New lessons from freshwater turtles and crucian carp |url=https://linkinghub.elsevier.com/retrieve/pii/S2451965020300028 |journal=Current Opinion in Endocrine and Metabolic Research |language=en |volume=11 |pages=55–64 |doi=10.1016/j.coemr.2020.01.002|url-access=subscription }}</ref>

== Inhibitors ==
There are several well-known [[drug]]s and [[toxin]]s that inhibit oxidative phosphorylation. Although any one of these toxins inhibits only one enzyme in the electron transport chain, inhibition of any step in this process will halt the rest of the process. For example, if [[oligomycin]] inhibits ATP synthase, protons cannot pass back into the mitochondrion.<ref name=Joshi/> As a result, the proton pumps are unable to operate, as the gradient becomes too strong for them to overcome. NADH is then no longer oxidized and the citric acid cycle ceases to operate because the concentration of NAD<sup>+</sup> falls below the concentration that these enzymes can use.

Many site-specific inhibitors of the electron transport chain have contributed to the present knowledge of mitochondrial respiration. Synthesis of ATP is also dependent on the electron transport chain, so all site-specific inhibitors also inhibit ATP formation. The fish poison [[rotenone]], the barbiturate drug [[amobarbital|amytal]], and the antibiotic [[piericidin A]] inhibit NADH and coenzyme Q.<ref name="Satyanarayana_2002">{{Cite book|title=Biochemistry| vauthors = Satyanarayana U |date=2002 |publisher=Books and Allied |isbn=81-87134-80-1 |edition=2nd|location=Kolkata, India|oclc=71209231}}</ref>

[[Carbon monoxide]], [[cyanide]], [[hydrogen sulfide]] and [[azide]] effectively inhibit cytochrome oxidase. Carbon monoxide reacts with the reduced form of the cytochrome while cyanide and azide react with the oxidised form. An antibiotic, [[antimycin A]], and [[dimercaprol|British anti-Lewisite]], an antidote used against chemical weapons, are the two important inhibitors of the site between cytochrome B and C1.<ref name="Satyanarayana_2002" />

{| class="wikitable" style="margin-left: auto; margin-right: auto;"
!Compounds
!Use
! Site of action
!Effect on oxidative phosphorylation
|-
|[[Cyanide]]<br />[[carbon monoxide|Carbon&nbsp;monoxide]]<br />[[Azide]]<br />[[Hydrogen sulfide]]
|align="center" |Poisons
|Complex IV
|Inhibit the electron transport chain by binding more strongly than oxygen to the [[iron|Fe]]–[[copper|Cu]] center in cytochrome c oxidase, preventing the reduction of oxygen.<ref>{{cite journal | vauthors = Tsubaki M | title = Fourier-transform infrared study of cyanide binding to the Fea3-CuB binuclear site of bovine heart cytochrome c oxidase: implication of the redox-linked conformational change at the binuclear site | journal = Biochemistry | volume = 32 | issue = 1 | pages = 164–173 | date = January 1993 | pmid = 8380331 | doi = 10.1021/bi00052a022 }}</ref>
|-
|[[Oligomycin]]
|align="center" |[[Antibiotic]]
|Complex V
||Inhibits ATP synthase by blocking the flow of protons through the F<sub>o</sub> subunit.<ref name=Joshi>{{cite journal | vauthors = Joshi S, Huang YG | title = ATP synthase complex from bovine heart mitochondria: the oligomycin sensitivity conferring protein is essential for dicyclohexyl carbodiimide-sensitive ATPase | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1067 | issue = 2 | pages = 255–258 | date = August 1991 | pmid = 1831660 | doi = 10.1016/0005-2736(91)90051-9 }}</ref>
|-
|[[Carbonyl cyanide m-chlorophenyl hydrazone|CCCP]]<br />[[2,4-Dinitrophenol]]
|align="center" |Poisons, weight-loss<ref group="N">DNP was extensively used as an [[anti-obesity medication]] in the 1930s but was ultimately discontinued due to its dangerous side effects. However, illicit use of the drug for this purpose continues today. See [[2,4-Dinitrophenol#Dieting aid]] for more information.</ref>
| Inner membrane
||[[Ionophore]]s that disrupt the proton gradient by carrying protons across a membrane. This ionophore [[uncouples]] proton pumping from ATP synthesis because it carries protons across the inner mitochondrial membrane.<ref>{{cite conference | vauthors = Heytler PG | title = Biomembranes Part F: Bioenergetics: Oxidative Phosphorylation | chapter = Uncouplers of oxidative phosphorylation | volume = 55 | pages = 462–472 | year = 1979 | pmid = 156853 | doi = 10.1016/0076-6879(79)55060-5 | isbn = 978-0-12-181955-2 | series = Methods in Enzymology | editor1= Sidney Fleischer | editor2= Lester Packer}}</ref>
|-
|[[Rotenone]]
|align="center" |[[Pesticide]]
|Complex I
||Prevents the transfer of electrons from complex I to ubiquinone by blocking the ubiquinone-binding site.<ref>{{cite journal | vauthors = Lambert AJ, Brand MD | title = Inhibitors of the quinone-binding site allow rapid superoxide production from mitochondrial NADH:ubiquinone oxidoreductase (complex I) | journal = The Journal of Biological Chemistry | volume = 279 | issue = 38 | pages = 39414–39420 | date = September 2004 | pmid = 15262965 | doi = 10.1074/jbc.M406576200 | s2cid = 26620903 | doi-access = free }}</ref>
|-
|[[Malonate]] and [[oxaloacetate]]
|align="center" | Poisons
|Complex II
||Competitive inhibitors of succinate dehydrogenase (complex II).<ref>{{cite journal | vauthors = Dervartanian DV, Veeger C | title = Studies on Succinate Dehydrogenase. I. Spectral Properties of the Purified Enzyme and Formation of Enzyme-Competitive Inhibitor Complexes | journal = Biochimica et Biophysica Acta (BBA) - Specialized Section on Enzymological Subjects | volume = 92 | issue = 2 | pages = 233–247 | date = November 1964 | pmid = 14249115 | doi = 10.1016/0926-6569(64)90182-8 }}</ref>
|-
|[[Antimycin A]]
|align="center" |[[Piscicide]]
|Complex III
||Binds to the Qi site of [[Coenzyme Q – cytochrome c reductase|cytochrome c reductase]], thereby inhibiting the [[oxidation]] of [[ubiquinol]].
|-
|}

Not all inhibitors of oxidative phosphorylation are toxins. In [[brown adipose tissue]], regulated proton channels called [[uncoupling protein]]s can uncouple respiration from ATP synthesis.<ref>{{cite journal | vauthors = Ricquier D, Bouillaud F | title = The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP | journal = The Biochemical Journal | volume = 345 | issue = Pt 2 | pages = 161–179 | date = January 2000 | pmid = 10620491 | pmc = 1220743 | doi = 10.1042/0264-6021:3450161 }}</ref> This rapid respiration produces heat, and is particularly important as a way of maintaining [[body temperature]] for [[hibernation|hibernating]] animals, although these proteins may also have a more general function in cells' responses to stress.<ref>{{cite journal | vauthors = Borecký J, Vercesi AE | title = Plant uncoupling mitochondrial protein and alternative oxidase: energy metabolism and stress | journal = Bioscience Reports | volume = 25 | issue = 3–4 | pages = 271–286 | year = 2005 | pmid = 16283557 | doi = 10.1007/s10540-005-2889-2 | s2cid = 18598358 }}</ref>

== History ==
{{further|History of biochemistry|History of molecular biology}}
The field of oxidative phosphorylation began with the report in 1906 by [[Arthur Harden]] of a vital role for phosphate in cellular [[fermentation (biochemistry)|fermentation]], but initially only [[sugar phosphates]] were known to be involved.<ref>{{cite journal | vauthors = Harden A, Young WJ |title=The alcoholic ferment of yeast-juice |journal=Proceedings of the Royal Society |volume=B |issue=77 |pages=405–20 |year=1906 |doi=10.1098/rspb.1906.0029 |doi-access=free }}</ref> However, in the early 1940s, the link between the oxidation of sugars and the generation of ATP was firmly established by [[Herman Kalckar]],<ref>{{cite journal | vauthors = Kalckar HM | title = Origins of the concept oxidative phosphorylation | journal = Molecular and Cellular Biochemistry | volume = 5 | issue = 1–2 | pages = 55–63 | date = November 1974 | pmid = 4279328 | doi = 10.1007/BF01874172 | s2cid = 26999163 }}</ref> confirming the central role of ATP in energy transfer that had been proposed by [[Fritz Albert Lipmann]] in 1941.<ref>{{cite journal | vauthors = Lipmann F |title=Metabolic generation and utilization of phosphate bond energy |journal=Adv Enzymol |volume=1 |pages=99–162 |year=1941 |doi=10.4159/harvard.9780674366701.c141|isbn=978-0-674-36670-1 }}</ref> Later, in 1949, Morris Friedkin and [[Albert L. Lehninger]] proved that the coenzyme NADH linked metabolic pathways such as the citric acid cycle and the synthesis of ATP.<ref>{{cite journal | vauthors = Friedkin M, Lehninger AL | title = Esterification of inorganic phosphate coupled to electron transport between dihydrodiphosphopyridine nucleotide and oxygen | journal = The Journal of Biological Chemistry | volume = 178 | issue = 2 | pages = 611–644 | date = April 1949 | pmid = 18116985 | doi = 10.1016/S0021-9258(18)56879-4 | url = http://www.jbc.org/cgi/reprint/178/2/611 | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20081216081441/http://www.jbc.org/cgi/reprint/178/2/611 | archive-date = 16 December 2008 }}</ref> The term ''oxidative phosphorylation'' was coined by {{Interlanguage link|Volodymyr Belitser|uk|3=Беліцер Володимир Олександрович}} in 1939.<ref>{{cite journal | vauthors = Kalckar HM | title = 50 years of biological research--from oxidative phosphorylation to energy requiring transport regulation | journal = Annual Review of Biochemistry | volume = 60 | pages = 1–37 | year = 1991 | pmid = 1883194 | doi = 10.1146/annurev.bi.60.070191.000245 | doi-access = free }}</ref><ref>{{Cite journal | vauthors = Belitser VA, Tsibakova ET | title = About phosphorilation mechanism coupled with respiration | journal = [[Biokhimiya]] | volume = 4| pages = 516–534 | year = 1939}}</ref>

For another twenty years, the mechanism by which ATP is generated remained mysterious, with scientists searching for an elusive "high-energy intermediate" that would link oxidation and phosphorylation reactions.<ref>{{cite journal | vauthors = Slater EC | title = Mechanism of phosphorylation in the respiratory chain | journal = Nature | volume = 172 | issue = 4387 | pages = 975–978 | date = November 1953 | pmid = 13111237 | doi = 10.1038/172975a0 | s2cid = 4153659 | bibcode = 1953Natur.172..975S }}</ref> This puzzle was solved by [[Peter D. Mitchell]] with the publication of the [[chemiosmotic theory]] in 1961.<ref>{{cite journal | vauthors = Mitchell P | title = Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism | journal = Nature | volume = 191 | issue = 4784 | pages = 144–148 | date = July 1961 | pmid = 13771349 | doi = 10.1038/191144a0 | s2cid = 1784050 | bibcode = 1961Natur.191..144M }}</ref> At first, this proposal was highly controversial, but it was slowly accepted and Mitchell was awarded a [[Nobel Prize|Nobel prize]] in 1978.<ref>{{cite book |title=Peter Mitchell and the Vital Force | vauthors = Saier Jr MH |oclc = 55202414}}</ref><ref>{{cite web |url=http://nobelprize.org/nobel_prizes/chemistry/laureates/1978/mitchell-lecture.pdf |title=David Keilin's Respiratory Chain Concept and Its Chemiosmotic Consequences |access-date=2007-07-21 | vauthors = Mitchell P |year=1978 |work=Nobel lecture |publisher=Nobel Foundation |url-status=live |archive-url=https://web.archive.org/web/20070927135238/http://nobelprize.org/nobel_prizes/chemistry/laureates/1978/mitchell-lecture.pdf |archive-date=2007-09-27 }}</ref> Subsequent research concentrated on purifying and characterizing the enzymes involved, with major contributions being made by [[David E. Green]] on the complexes of the electron-transport chain, as well as [[Efraim Racker]] on the ATP synthase.<ref>{{cite journal | vauthors = Pullman ME, Penefsky HS, Datta A, Racker E | title = Partial resolution of the enzymes catalyzing oxidative phosphorylation. I. Purification and properties of soluble dinitrophenol-stimulated adenosine triphosphatase | journal = The Journal of Biological Chemistry | volume = 235 | issue = 11 | pages = 3322–3329 | date = November 1960 | pmid = 13738472 | doi = 10.1016/S0021-9258(20)81361-1 | url = http://www.jbc.org/cgi/reprint/235/11/3322 | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20070929091858/http://www.jbc.org/cgi/reprint/235/11/3322 | archive-date = 29 September 2007 }}</ref> A critical step towards solving the mechanism of the ATP synthase was provided by [[Paul D. Boyer]], by his development in 1973 of the "binding change" mechanism, followed by his radical proposal of rotational catalysis in 1982.<ref name=Gresser/><ref>{{cite journal | vauthors = Boyer PD, Cross RL, Momsen W | title = A new concept for energy coupling in oxidative phosphorylation based on a molecular explanation of the oxygen exchange reactions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 70 | issue = 10 | pages = 2837–2839 | date = October 1973 | pmid = 4517936 | pmc = 427120 | doi = 10.1073/pnas.70.10.2837 | doi-access = free | bibcode = 1973PNAS...70.2837B }}</ref> More recent work has included [[x-ray crystallography|structural studies]] on the enzymes involved in oxidative phosphorylation by [[John E. Walker]], with Walker and Boyer being awarded a Nobel Prize in 1997.<ref>{{cite web |url=http://nobelprize.org/nobel_prizes/chemistry/laureates/1997/ |title=The Nobel Prize in Chemistry 1997 |access-date=2007-07-21 |publisher=Nobel Foundation |url-status=live |archive-url=https://web.archive.org/web/20170325181904/http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1997/ |archive-date=2017-03-25 }}</ref>

== See also ==
*[[Respirometry]]
*[[TIM/TOM Complex]]

==Notes==
{{Reflist|group="N"}}

== References ==
{{Reflist|32em}}

== Further reading ==

=== Introductory ===
* {{cite book| vauthors = Nelson DL, Cox MM |title=Lehninger Principles of Biochemistry|edition=4th|publisher=W. H. Freeman|year=2004|isbn=0-7167-4339-6|url-access=registration|url=https://archive.org/details/lehningerprincip00lehn_0}}
* {{cite book| vauthors = Schneider ED, Sagan D|title=Into the Cool: Energy Flow, Thermodynamics and Life|edition=1st|publisher=University of Chicago Press|year=2006|isbn=0-226-73937-6}}
* {{cite book| vauthors = Lane N |title=Power, Sex, Suicide: Mitochondria and the Meaning of Life |edition=1st|publisher=Oxford University Press, USA |year=2006|isbn=0-19-920564-7|author-link=Nick Lane }}

=== Advanced ===
* {{cite book| vauthors = Nicholls DG, Ferguson SJ |title=Bioenergetics 3 |edition=1st|publisher=Academic Press|year=2002|isbn=0-12-518121-3}}
* {{cite book| vauthors = Haynie D |title=Biological Thermodynamics |edition=1st|publisher=Cambridge University Press|year=2001|isbn=0-521-79549-4}}
* {{cite book| vauthors = Rajan SS |title=Introduction to Bioenergetics |edition=1st|publisher=Anmol |year=2003|isbn=81-261-1364-2}}
* {{cite book| veditors = Wikstrom M |title=Biophysical and Structural Aspects of Bioenergetics |edition=1st|publisher=Royal Society of Chemistry |year=2005|isbn=0-85404-346-2}}

=== General resources ===
*[http://www.wiley.com/legacy/college/boyer/0470003790/animations/electron_transport/electron_transport.htm Animated diagrams illustrating oxidative phosphorylation] [[John Wiley & Sons|Wiley and Co]] ''Concepts in Biochemistry''
*[http://www.life.uiuc.edu/crofts/bioph354/ On-line biophysics lectures] {{Webarchive|url=https://web.archive.org/web/20090502064759/http://www.life.uiuc.edu/crofts/bioph354/ |date=2009-05-02 }} Antony Crofts, [[University of Illinois at Urbana–Champaign]]
*[https://www.youtube.com/watch?v=PjdPTY1wHdQ ATP Synthase] Graham Johnson

=== Structural resources ===
*[[Protein Data Bank|PDB]] molecule of the month:
**[http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb72_1.html ATP synthase] {{Webarchive|url=https://web.archive.org/web/20200724160107/http://www.rcsb.org/pdb/static.do?p=education_discussion%2Fmolecule_of_the_month%2Fpdb72_1.html |date=2020-07-24 }}
**[http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb36_1.html Cytochrome c] {{Webarchive|url=https://web.archive.org/web/20200724160103/http://www.rcsb.org/pdb/static.do?p=education_discussion%2Fmolecule_of_the_month%2Fpdb36_1.html |date=2020-07-24 }}
**[http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb5_1.html Cytochrome c oxidase] {{Webarchive|url=https://web.archive.org/web/20200724160107/http://www.rcsb.org/pdb/static.do?p=education_discussion%2Fmolecule_of_the_month%2Fpdb5_1.html |date=2020-07-24 }}
*Interactive molecular models at [[Universidade Fernando Pessoa]]:
**[https://web.archive.org/web/20090112031333/http://www2.ufp.pt/~pedros/anim/2frame-ien.htm NADH dehydrogenase]
**[https://web.archive.org/web/20090111212436/http://www2.ufp.pt/~pedros/anim/2frame-iien.htm succinate dehydrogenase]
**[https://web.archive.org/web/20090112035125/http://www2.ufp.pt/~pedros/anim/2frame-iiien.htm Coenzyme Q - cytochrome c reductase]
**[https://web.archive.org/web/20090111220321/http://www2.ufp.pt/~pedros/anim/2frame-iven.htm cytochrome c oxidase]

{{Electron transport chain}}
{{Cellular respiration}}
{{MetabolismMap}}
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