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| {{MitoPedia
| | #REDIRECT [[Electron-transfer-pathway state]] |
| |abbr=n.a.
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| |description=[[File:SUIT-catg FNSGpCIV.jpg|right|400px]]
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| '''ETS pathway types''' are linked to ETS substrate types in mitochondrial [[SUIT protocols]]. Mitochondrial pathways are stimulated by fuel substrates (CHNO) feeding electrons into the [[electron transfer system]] (ETS) at different levels of integration and in the presence or absence of inhibitors acting on specific enzymes in these pathways. Distinction of five ETS pathway types provides the rationale for defining [[categories of SUIT protocols]].
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| '''ETS pathway type 1''' is stimulated by artificial electron donors (e.g. [[TMPD]], Tm) essentially bypassing the ETS, reducing [[cytochrome c |cytochrome ''c'']] and feeding electrons to cytochrome ''c'' oxidase (CIV) or alternative oxidases (single enzymatic step), with oxygen as the terminal electron acceptor.
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| '''ETS pathway type 2''' is stimulated by duroquinol (DQ) feeding electrons into Complex III (CIII) with further electron transfer to CIV and oxygen.
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| '''ETS pathways type 3''' feed electrons from [[NADH]], [[FADH2 |FADH<sub>2</sub>]], [[succinate]], [[glycerophosphate]] into respiratory complexes directly upstream of the [[Q-junction]]. NADH is the substrate of [[Complex I]] (CI). FADH<sub>2</sub> is the substrate of [[electron transferring flavoprotein]] (CETF) localized on the inner side of the inner mt-membrane. Succinate is the substrate of [[succinate dehydrogenase]] (SDH, CII) localized on the inner side of the inner mt-membrane. [[Glycerophosphate]] is the substrate of [[glycerophosphate dehydrogenase complex]] (CGpDH) localized on the outer face of the inner mt-membrane. [[Choline]] is the type 3 substrate of [[choline dehydrogenase]].
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| '''ETS pathway type 4''' feeds electrons into dehydrogenases and enzyme systems upstream of the type 3 pathway level. Electron transfer from type 4 substrates (N) converges at the [[N-junction]]. Representative '''N-junction substrates''' are pyruvate, glutamate and malate, and also citrate, oxoglutarate and others. The corresponding dehydrogenases ([[Pyruvate dehydrogenase |PDH]], [[Glutamate dehydrogenase |GDH]], [[Malate dehydrogenase |MDH]] and [[Malic enzyme |mtME]]; [[Isocitrate dehydrogenase |IDH]], [[Oxoglutarate dehydrogenase |OgDH]]) generate NADH, the substrate of [[Complex I]] (CI). Fatty acids supporting converging electron transfer to the [[F-junction]] might also considered as type 4 substrates. However, the requirement of a combined operation of the [[F-junction]] and [[N-junction]] puts type F substrates to a higher level of pathway integration.
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| '''ETS pathway type 5''' feeds electrons into dehydrogenases and enzyme systems upstream of the type 3 pathway level with an obligatory combination of the [[F-junction]] and [[N-junction]]. '''F-junction substrates''' are fatty acids involved in β-oxidation, generating (enzyme-bound) FADH<sub>2</sub>, the substrate of [[electron transferring flavoprotein]] (CETF). Succinate does not belong to the type 4 substrates, since FADH<sub>2</sub> is the ''product'' of CII, whereas FADH<sub>2</sub> is the ''substrate'' of CETF. Fatty acid oxidation (FAO) not only depends on electron transfer through the F-junction (which is typically rate-limiting) but simultaneously generates NADH and thus depends on N-junction throughput. Hence FAO can be inhibited completely by inhibition of Complex I (CI). In addition and independent of this source of NADH, the N-junction substrate malate is required as a co-substrate for FAO in mt-preparations, since accumulation of AcetylCoA inhibits FAO in the absence of malate. Malate is oxidized in a reaction catalyzed by malate dehydrogenase to oxaloacetate (yielding NADH), which then stimulates the entry of AcetylCo into the TCA cycle catalyzed by citrate synthase.
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| |info=[[Gnaiger 2014 MitoPathways]]
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| }}
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| {{MitoPedia concepts
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| |mitopedia concept=MiP concept, Respiratory state, SUIT concept
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| }}
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| {{MitoPedia topics
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| |mitopedia topic=Substrate and metabolite
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| }}
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| Contributed by [[Gnaiger E]] 2016-02-01; edited 2016-02-10, 2016-03-29, 2016-08-20, 2016-09-10, 2016-11-08.
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| == ETS substrate types on different pathway levels ==
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| :::* ETS substrates type 5 on the pathway level of converging FADH<sub>2</sub> and NADH-linked dehydrogenases, including beta-oxidation and segments of the TCA cycle:
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| ::::'''F''': [[F-junction]] substrates, FADH<sub>2</sub>-linked, fatty acids (FAO)
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| :::* ETS substrates type 4 on the pathway level of converging NADH-linked dehydrogenases, including the TCA cycle:
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| ::::'''N''': [[N-junction]] substrates, NADH-linked (and hence downstream 'CI-linked')
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| :::* ETS substrates type 3 on the pathway level of electron transfer complexes converging at the Q-junction:
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| ::::'''Q''': [[Q-junction]] substrates
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| ::::# '''[[NADH]], substrate of CI
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| ::::# '''[[FADH2 |FADH<sub>2</sub>]], substrate of CETF
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| ::::# '''S''': [[Succinate]], substrate of CII
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| ::::# '''Gp''': [[Glycerophosphate]], substrate of CGpDH
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| ::::# '''Choline''': substrate of [[choline dehydrogenase]]
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| :::* ETS substrates type 1 on the single step level of cytochrome ''c'' oxidase (CIV), the terminal step in the aerobic electron transfer system:
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| :::: '''Tm''': Artificial electron transfer susbstrate [[TMPD]] (Tm) maintained in a reduced state by [[ascorbate]] (As) and reducing cytochrome ''c'' as the substrate of [[CIV]].
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