Editing Electron transport chain (section)

==Mitochondrial electron transport chains==
[[Image:Mitochondrial electron transport chain—Etc4.svg|thumb|300px|The electron transport chain in the [[mitochondrion]] is the site of [[oxidative phosphorylation]] in [[eukaryote]]s. It mediates the reaction between [[NADH]] or [[Succinic acid|succinate]] generated in the [[citric acid cycle]] and oxygen to power [[ATP synthase]].]]
Most [[eukaryotic]] cells have [[mitochondria]], which produce ATP from reactions of oxygen with products of the [[citric acid cycle]], [[fatty acid metabolism]], and [[amino acid metabolism]]. At the [[inner mitochondrial membrane]], electrons from [[Nicotinamide adenine dinucleotide|NADH]] and [[Flavin adenine dinucleotide|FADH{{sub|2}}]] pass through the electron transport chain to oxygen, which provides the energy driving the process as it is reduced to water.<ref>{{Cite journal| vauthors = Waldenström JG |date=2009-04-24|title=Biochemistry. By Lubert Stryer|journal=Acta Medica Scandinavica|volume=198|issue=1–6|pages=436|doi=10.1111/j.0954-6820.1975.tb19571.x|issn=0001-6101}}</ref> The electron transport chain comprises an [[enzymatic]] series of electron donors and acceptors. Each [[electron donor]] will pass electrons to an [[Electron acceptor|acceptor]] of higher redox potential, which in turn donates these electrons to another acceptor, a process that continues down the series until electrons are passed to oxygen, the terminal electron acceptor in the chain. Each reaction releases energy because a higher-energy donor and acceptor convert to lower-energy products. Via the transferred electrons, this energy is used to generate a [[proton gradient]] across the mitochondrial membrane by [[proton pump|"pumping" protons]] into the intermembrane space, producing a state of higher free energy that has the potential to do work. This entire process is called [[oxidative phosphorylation]] since ADP is phosphorylated to ATP by using the electrochemical gradient that the redox reactions of the electron transport chain have established driven by energy-releasing reactions of oxygen.{{cn|date=January 2025}}

===Mitochondrial redox carriers===<!-- This section is linked from [[Mitochondrion]] -->
Energy associated with the transfer of electrons down the electron transport chain is used to pump protons from the [[mitochondrial matrix]] into the intermembrane space, creating an [[Electrochemical gradient|electrochemical proton gradient]] ([[Oxidative phosphorylation#Chemiosmosis|ΔpH]]) across the inner mitochondrial membrane. This proton gradient is largely but not exclusively responsible for the mitochondrial [[membrane potential]] (ΔΨ{{sub|M}}).<ref name="Zorova">{{cite journal | vauthors = Zorova LD, Popkov VA, Plotnikov EY, Silachev DN, Pevzner IB, Jankauskas SS, Babenko VA, Zorov SD, Balakireva AV, Juhaszova M, Sollott SJ, Zorov DB | display-authors = 6 | title = Mitochondrial membrane potential | journal = Analytical Biochemistry | volume = 552 | pages = 50–59 | date = July 2018 | pmid = 28711444 | pmc = 5792320 | doi = 10.1016/j.ab.2017.07.009 }}</ref> It allows [[ATP synthase]] to use the flow of H<sup>+</sup> through the enzyme back into the matrix to generate ATP from [[adenosine diphosphate]] (ADP) and [[inorganic phosphate]]. Complex I (NADH coenzyme Q reductase; labeled I) accepts electrons from the [[Krebs cycle]] electron carrier [[Nicotinamide adenine dinucleotide|nicotinamide adenine dinucleotide (NADH)]], and passes them to [[coenzyme Q]] ([[ubiquinone]]; labeled Q), which also receives electrons from Complex II ([[succinate dehydrogenase]]; labeled II). Q passes electrons to Complex III ([[cytochrome bc1 complex|cytochrome bc<sub>1</sub> complex]]; labeled III), which passes them to [[cytochrome c|cytochrome ''c'']] (cyt ''c''). Cyt ''c'' passes electrons to Complex IV ([[cytochrome c oxidase|cytochrome ''c'' oxidase]]; labeled IV).{{cn|date=January 2025}}

Four membrane-bound complexes have been identified in mitochondria. Each is an extremely complex [[Transmembrane protein|transmembrane]] structure that is embedded in the inner membrane. Three of them are [[proton pump]]s. The structures are electrically connected by [[lipid-soluble]] electron carriers and water-soluble electron carriers. The overall electron transport chain can be summarized as follows:

 '''NADH, H{{sup|+}}''' → '''''Complex I''''' → '''Q''' → '''''Complex III''''' → '''cytochrome ''c'' '''→ '''''Complex IV''''' → '''H{{sub|2}}O'''
                        ↑
                    '''''Complex II'''''
                        ↑
                    '''Succinate'''

====Complex I====
{{Further|Respiratory complex I}}
In [[Respiratory complex I|Complex I]] (NADH ubiquinone oxidoreductase, Type I NADH dehydrogenase, or mitochondrial complex I; {{EC number|1.6.5.3}}), two electrons are removed from NADH and transferred to a lipid-soluble carrier, ubiquinone (Q). The reduced product, ubiquinol (QH{{sub|2}}), freely diffuses within the membrane, and Complex I translocates four protons (H{{sup|+}}) across the membrane, thus producing a proton gradient. Complex I is one of the main sites at which premature [[electron leakage]] to oxygen occurs, thus being one of the main sites of production of [[superoxide]].<ref name = "Lauren">Lauren, Biochemistry, Johnson/Cole, 2010, pp 598-611</ref>

The pathway of electrons is as follows:

[[NADH]] is oxidized to NAD{{sup|+}}, by reducing [[flavin mononucleotide]] to FMNH{{sub|2}} in one two-electron step. FMNH{{sub|2}} is then oxidized in two one-electron steps, through a [[Ubiquinone#Chemical properties|semiquinone]] intermediate. Each electron thus transfers from the FMNH{{sub|2}} to an [[iron–sulfur cluster|Fe–S cluster]], from the Fe-S cluster to ubiquinone (Q). Transfer of the first electron results in the free-radical ([[Ubiquinone#Chemical properties|semiquinone]]) form of Q, and transfer of the second electron reduces the semiquinone form to the ubiquinol form, QH{{sub|2}}. During this process, four protons are translocated from the mitochondrial matrix to the intermembrane space.<ref name = "Garrett">Garrett & Grisham, Biochemistry, Brooks/Cole, 2010, pp 598-611</ref> As the electrons move through the complex an electron current is produced along the 180 [[Angstrom]] width of the complex within the membrane. This current powers the [[active transport]] of four protons to the intermembrane space per two electrons from NADH.<ref>{{Cite book|title=biochemistry| vauthors = Garrett R, Grisham CM |year=2016|isbn=978-1-305-57720-6| location = Boston | publisher = Cengage |pages=687}}</ref>

====Complex II====
In [[Respiratory complex II|Complex II]] ([[succinate dehydrogenase]] or succinate-CoQ reductase; {{EC number|1.3.5.1}}) additional electrons are delivered into the [[quinone]] pool (Q) originating from succinate and transferred (via [[Flavin adenine dinucleotide|flavin adenine dinucleotide (FAD)]]) to Q. Complex II consists of four protein subunits: succinate dehydrogenase (SDHA); succinate dehydrogenase [ubiquinone] iron–sulfur subunit mitochondrial (SDHB); succinate dehydrogenase complex subunit C (SDHC); and succinate dehydrogenase complex subunit D (SDHD). Other electron donors (e.g., fatty acids and glycerol 3-phosphate) also direct electrons into Q (via FAD). Complex II is a parallel electron transport pathway to Complex I, but unlike Complex I, no protons are transported to the intermembrane space in this pathway. Therefore, the pathway through Complex II contributes less energy to the overall electron transport chain process.{{cn|date=January 2025}}

====Complex III====
In [[Complex III]] ([[cytochrome bc1 complex|cytochrome ''bc<sub>1</sub>'' complex]] or CoQH{{sub|2}}-cytochrome ''c'' reductase; {{EC number|1.10.2.2}}), the [[Q cycle|Q-cycle]] contributes to the proton gradient by an asymmetric absorption/release of protons. Two electrons are removed from QH{{sub|2}} at the Q<sub>O</sub> site and sequentially transferred to two molecules of [[cytochrome c|cytochrome ''c'']], a water-soluble electron carrier located within the intermembrane space. The two other electrons sequentially pass across the protein to the Q<sub>i</sub> site where the quinone part of ubiquinone is reduced to quinol. A proton gradient is formed by one quinol (<chem>2H+2e-</chem>) oxidations at the Q<sub>o</sub> site to form one quinone (<chem>2H+2e-</chem>) at the Q<sub>i</sub> site. (In total, four protons are translocated: two protons reduce quinone to quinol and two protons are released from two ubiquinol molecules.){{cn|date=January 2025}}
: <chem>  QH2 + 2</chem><math> \text{ cytochrome }c</math><chem>(Fe^{III}) + 2 H</chem><math>^+_\text{in}</math><chem> -> Q + 2</chem><math> \text{ cytochrome }c</math><chem>(Fe^{II}) + 4 H</chem><math>^+_\text{out}</math>

When electron transfer is reduced (by a high membrane potential or respiratory inhibitors such as [[antimycin A]]), Complex III may leak electrons to [[molecular oxygen]], resulting in [[superoxide]] formation.

This complex is inhibited by [[dimercaprol]] (British Anti-Lewisite, BAL), [[naphthoquinone]] and antimycin.

====Complex IV====
In [[Complex IV]] ([[cytochrome c oxidase|cytochrome ''c'' oxidase]]; {{EC number|1.9.3.1}}), sometimes called cytochrome AA3, four electrons are removed from four molecules of [[cytochrome c|cytochrome ''c'']] and transferred to molecular oxygen (O{{sub|2}}) and four protons, producing two molecules of water. The complex contains coordinated copper ions and several heme groups. At the same time, eight protons are removed from the mitochondrial matrix (although only four are translocated across the membrane), contributing to the proton gradient. The exact details of proton pumping in Complex IV are still under study.<ref name=":1">{{Cite book|last=Stryer.|title=Biochemistry|publisher=toppan|oclc=785100491}}</ref> [[Cyanide]] is an inhibitor of Complex IV.{{cn|date=January 2025}}

===Coupling with oxidative phosphorylation===
[[File:ATP-Synthase.svg|thumb|240px|Depiction of [[ATP synthase]], the site of oxidative phosphorylation to generate ATP.]]
According to the [[chemiosmosis|chemiosmotic coupling hypothesis]], proposed by [[Nobel Prize in Chemistry]] winner [[Peter D. Mitchell]], the electron transport chain and [[oxidative phosphorylation]] are coupled by a proton gradient across the inner mitochondrial membrane. The efflux of protons from the mitochondrial matrix creates an [[electrochemical gradient]] (proton gradient). This gradient is used by the F{{sub|O}}F{{sub|1}} [[ATP synthase]] complex to make ATP via oxidative phosphorylation. ATP synthase is sometimes described as ''Complex V'' of the electron transport chain.<ref>{{cite journal | vauthors = Jonckheere AI, Smeitink JA, Rodenburg RJ | title = Mitochondrial ATP synthase: architecture, function and pathology | journal = Journal of Inherited Metabolic Disease | volume = 35 | issue = 2 | pages = 211–25 | date = March 2012 | pmid = 21874297 | pmc = 3278611 | doi = 10.1007/s10545-011-9382-9 }}</ref> The F{{sub|O}} component of [[ATP synthase]] acts as an [[ion channel]] that provides for a proton flux back into the mitochondrial matrix. It is composed of a, b and c subunits. Protons in the inter-membrane space of mitochondria first enter the ATP synthase complex through an ''a'' subunit channel. Then protons move to the c subunits.<ref name=":0">{{Cite book|title=Biochemistry| vauthors = Garrett RH, Grisham CM |publisher=Cengage learning|year=2012|isbn=978-1-133-10629-6|edition=5th|pages=664}}</ref> The number of c subunits determines how many protons are required to make the F{{sub|O}} turn one full revolution. For example, in humans, there are 8 c subunits, thus 8 protons are required.<ref>{{cite journal | vauthors = Fillingame RH, Angevine CM, Dmitriev OY | title = Mechanics of coupling proton movements to c-ring rotation in ATP synthase | journal = FEBS Letters | volume = 555 | issue = 1 | pages = 29–34 | date = November 2003 | pmid = 14630314 | doi = 10.1016/S0014-5793(03)01101-3 | s2cid = 38896804 | doi-access = free }}</ref> After ''c'' subunits, protons finally enter the matrix through an ''a'' subunit channel that opens into the mitochondrial matrix.<ref name=":0" /> This reflux releases [[Gibb's free energy|free energy]] produced during the generation of the oxidized forms of the electron carriers (NAD{{sup|+}} and Q) with energy provided by O{{sub|2}}. The free energy is used to drive ATP synthesis, catalyzed by the F{{sub|1}} component of the complex.<ref>{{Cite journal|last1=Berg|first1=Jeremy M.|last2=Tymoczko|first2=John L.|last3=Stryer|first3=Lubert | name-list-style = vanc |date=2002-01-01|title=A Proton Gradient Powers the Synthesis of ATP|url=https://www.ncbi.nlm.nih.gov/books/NBK22388/|language=en}}</ref><br>Coupling with oxidative phosphorylation is a key step for ATP production. However, in specific cases, uncoupling the two processes may be biologically useful. The uncoupling protein, [[thermogenin]]—present in the inner mitochondrial membrane of [[brown adipose tissue]]—provides for an alternative flow of protons back to the inner mitochondrial matrix. Thyroxine is also a natural uncoupler. This alternative flow results in [[thermogenesis]] rather than ATP production.<ref>{{cite journal | vauthors = Cannon B, Nedergaard J | title = Brown adipose tissue: function and physiological significance | journal = Physiological Reviews | volume = 84 | issue = 1 | pages = 277–359 | date = January 2004 | pmid = 14715917 | doi = 10.1152/physrev.00015.2003 | url = http://physrev.physiology.org/content/84/1/277 | url-access = subscription }}</ref>

=== Reverse electron flow ===
[[Reverse electron flow]] is the transfer of electrons through the electron transport chain through the reverse redox reactions. Usually requiring a significant amount of energy to be used, this can reduce the oxidized forms of electron donors. For example, NAD<sup>+</sup> can be reduced to NADH by Complex I.<ref>{{cite book |last1=Kim|first1=Byung Hong |last2=Gadd|first2=Geoffrey Michael | name-list-style = vanc |chapter=Introduction to bacterial physiology and metabolism| title =Bacterial Physiology and Metabolism|pages=1–6|publisher=Cambridge University Press|isbn=978-0-511-79046-1|year=2008|doi=10.1017/cbo9780511790461.002}}</ref> There are several factors that have been shown to induce reverse electron flow. However, more work needs to be done to confirm this. One example is blockage of ATP synthase, resulting in a build-up of protons and therefore a higher [[proton-motive force]], inducing [[reverse electron flow]].<ref>{{cite journal | vauthors = Mills EL, Kelly B, Logan A, Costa AS, Varma M, Bryant CE, Tourlomousis P, Däbritz JH, Gottlieb E, Latorre I, Corr SC, McManus G, Ryan D, Jacobs HT, Szibor M, Xavier RJ, Braun T, Frezza C, Murphy MP, O'Neill LA | display-authors = 6 | title = Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages | journal = Cell | volume = 167 | issue = 2 | pages = 457–470.e13 | date = October 2016 | pmid = 27667687 | doi = 10.1016/j.cell.2016.08.064 | pmc = 5863951 | doi-access = free }}</ref>