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Difference between revisions of "Uncoupler"

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{{MitoPedia
{{MitoPedia
|abbr=U
|abbr=U
|description=An '''uncoupler''' is a protonophore ([[CCCP]], [[FCCP]], [[DNP]]) which cycles across the inner mt-membrane with transport of protons and dissipation of the electrochemical proton gradient. Mild uncoupling may be induced at low uncoupler concentrations, the noncoupled state of [[ET capacity]] is obtained at optimum uncoupler concentration for maximum flux, whereas at higher concentrations an uncoupler-induced inhibition is observed.  
|description=An '''uncoupler''' is a protonophore ([[CCCP]], [[FCCP]], [[DNP]]) which cycles across the inner mt-membrane with transport of protons and dissipation of the electrochemical proton gradient. Mild uncoupling may be induced at low uncoupler concentrations, the noncoupled state of [[ET capacity]] is obtained at optimum uncoupler concentration for maximum flux, whereas at higher concentrations an uncoupler-induced inhibition is observed.
» [[#Is_respiration_uncoupled_-_noncoupled_-_dyscoupled.3F |'''MiPNet article''']]
|info=[[Noncoupled respiration]]
|type=Chemicals
|methods_type=Chemicals
|topics_type=Chemicals
}}
}}
{{MitoPedia concepts}}
{{MitoPedia methods
|type=Chemicals
}}
{{MitoPedia O2k and high-resolution respirometry}}
{{MitoPedia topics
|mitopedia topic=Uncoupler
|type=Chemicals
}}
[[File:Questions.jpg|left|40px]]
<br />
[[File:Expand.png|right|45px |Click to expand or collaps]]
<div class="toccolours mw-collapsible mw-collapsed">
::: <span style="font-size:105%; color:##424242">'''» Keywords'''</span>
<div class="mw-collapsible-content">
::: '''Specific'''
::::» [[Talk:Rogers_2011_PlosOne#Uncoupled_flux_does_not_reflect_electron_transfer_system_capacity|Artefacts by single dose uncoupling]]
::::» [[ATP synthase]]
::::» [[CCCP]]
::::» [[Coupling control protocol]]
::::» [[Talk:Uncoupler|Discussion: Uncoupler]]
::::» [[DNP]]
::::» [[Dyscoupled respiration]]
::::» [[ET capacity]]
::::» [[ET-pathway coupling efficiency]]
::::» [[ET capacity]] 
::::» [[FCCP]]
::::» [[Noncoupled respiration]]
::::» [[Optimum uncoupler concentration]]
::::» [[ROUTINE control ratio]]
::::» [[Uncoupler control ratio]]
::::» [[Uncoupling proteins]]
::::» [[Uncoupling protein 1]]
::: '''General'''
::::» [[Adenine nucleotide translocase]]
::::» [[Adenine_nucleotides|Adenylates]]
::::» [[Cytochrome c release | Cytochrome ''c'' release]]
::::» [[Electron transfer-pathway]]
::::» [[Flux control factor]]s
::::» [[Flux control ratio]]s
::::» [[Inhibitors]]
::::» [[LEAK control ratio]]
::::» [[LEAK respiration]]
::::» [[Mitochondrial preparations]]
::::» [[MiR06]]
::::» [[OXPHOS]]
::::» [[OXPHOS control ratio]]
::::» [[Oxygen flux]]
::::» [[Phosphorylation]]
::::» [[Proton leak]]
::::» [[Proton slip]]
::::» [[Respiratory acceptor control ratio]]
::::» [[ROUTINE respiration]]
::::» [[ROUTINE state]]
::::» [[State 3]]
::::» [[State 4]]
::::» [[TIP2k]]
</div>
</div>
<br />
__TOC__
= List of uncouplers =
= List of uncouplers =
::::» [[MitoPedia: Uncouplers]]
::::» [[MitoPedia: Uncouplers]]


 
{{Keywords: Uncoupling}}
= Is respiration uncoupled - noncoupled - dyscoupled? =
{{Keywords: Force and membrane potential}}
:::: or loosely coupled?
{{Publication
|title=Gnaiger E (2014) Is respiration uncoupled - noncoupled - dyscoupled? Mitochondr Physiol Network 2014-04-18.
|info=
|authors=OROBOROS
|year=2014
|journal=MiPNet
|abstract=Coupling of [[OXPHOS]] represents a complex concept. '''Uncoupler''' titrations provide an invaluable experimental tool.
|mipnetlab=AT Innsbruck Gnaiger E
}}
{{Labeling
|topics=Coupling efficiency;uncoupling
|couplingstates=LEAK, ET
|instruments=Theory
}}
== Uncoupled respiration ==
 
:::: The '''uncoupled''' part of '''respiration''' of ''[[OXPHOS capacity]]'' pumps protons to compensate for intrinsic uncoupling, which is a property of ('''''a''''') the inner mt-membrane ([[proton leak]]), ('''''b''''') the proton pumps ([[proton slip]]; decoupling), and ('''''c''''') is regulated by molecular uncouplers ([[uncoupling proteins]], UCP1).  Uncoupled and [[dyscoupled respiration]] are summarized as [[LEAK respiration]].  In contrast, [[noncoupled respiration]] is induced [[optimum uncoupler concentration|experimentally]] for evaluation of [[ET capacity]].<ref>Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. Int J Biochem Cell Biol 41:1837-45. [[Gnaiger 2009 Int J Biochem Cell Biol |»Bioblast link«]]</ref>,<ref>Gnaiger E (2014) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. 4th ed. Mitochondr Physiol Network 19.12. OROBOROS MiPNet Publications, Innsbruck:80 pp. [[Gnaiger 2014 MitoPathways |»Bioblast link«]]</ref>
 
=== Uncoupled respiration - intrinsic ===
:::: '''Uncoupling''' is used for ''intrinsic'' (physiological) uncoupling, appreciating the fact that we do not (never??) find mitochondria to be fully (mechanistically) coupled. In the [[ROUTINE]] (intact cells) and [[OXPHOS]] (mt-preparations) state of respiration, mitochondria are both, partially coupled and partially uncoupled. The uncoupled part of OXPHOS capacity is larger than [[LEAK]] respiration evaluated in the LEAK state after inhibition of [[ATP synthase]] or [[adenine nucleotide translocase]]. This is due to the increase of mt-membrane potential in the LEAK versus OXPHOS state, causing a corresponding increase of the proton leak driven by the higher proton motive force. As an approximation, however, the difference ''E''-''L'' yields an estimate of the physiological scope of uncoupling, or the pathological scope of dyscoupling.
 
=== Uncoupled respiration - experimental ===
:::: '''Uncoupling''' is also used for directed experimental interventions to lower the degree of coupling, typically by application of established [[uncoupler]]s (experimental use of a pharmacological intervention), less typical by freeze-thawing or mechanical crashing of mitochondrial membranes. Such ''experimental'' uncoupling can induce stimulation or inhibition of respiration.
 
=== Noncoupled respiration ===
:::: '''[[Noncoupled respiration]]''' is distinguished from general (pharmacological or mechanical) uncoupled respiration, to give a label to an effort to reach the ''fully uncoupled'' (non-coupled) state without inhibiting respiration. Non-coupled respiration, therefore, yields an estimate of [[ET capacity]]. Experimentally uncoupled respiration may fail to yield an estimate of ET capacity, due to inhibition of respiration above optimum uncoupler concentrations or insufficient stimulation by sub-optimal uncoupler concentrations. '''[[Optimum uncoupler concentration]]s''' for evaluation of (noncoupled) ET capacity require inhibitor titrations <ref>Steinlechner-Maran R, Eberl T, Kunc M, Margreiter R, Gnaiger E (1996) Oxygen dependence of respiration in coupled and uncoupled endothelial cells. Am J Physiol Cell Physiol 271:C2053-61. [[Steinlechner-Maran_1996_Am J Physiol Cell Physiol |»Bioblast link«]]</ref>,<ref> Hütter E, Renner K, Pfister G, Stöckl P, Jansen-Dürr P, Gnaiger E (2004) Senescence-associated changes in respiration and oxidative phosphorylation in primary human fibroblasts. Biochem J 380: 919-928. [[Huetter_2004_Biochem J |»Bioblast link«]]</ref>,<ref> Gnaiger E (2008) Polarographic oxygen sensors, the oxygraph and high-resolution respirometry to assess mitochondrial function. In: Mitochondrial Dysfunction in Drug-Induced Toxicity (Dykens JA, Will Y, eds) John Wiley:327-52. [[Gnaiger_2008_POS |»Bioblast link«]]</ref>
 
 
=== Dyscoupled respiration ===
:::: '''[[Dyscoupled respiration]]''' is distinguished from intrinsically (physiologically) uncoupled and from extrinsic experimentally uncoupled respiration as an indication of ''extrinsic'' uncoupling (pathological, toxicological, pharmacological by agents that are not specifically applied to induce uncoupling, but are tested for their potential dyscoupling effect). Dyscoupling indicates a mitochondrial dysfunction. <ref> Kuznetsov AV, Schneeberger S, Seiler R, Brandacher G, Mark W, Steurer W, Saks V, Usson Y, Margreiter R, Gnaiger E (2004) Mitochondrial defects and heterogeneous cytochrome c release after cardiac cold ischemia and reperfusion. Am J Physiol Heart Circ Physiol 286:H1633–41. [[Kuznetsov_2004_Am_J_Physiol_Heart_Circ_Physiol |»Bioblast link«]]</ref>
 
 
[[Talk:Uncoupler|Continue the discussion]]
 
 
== Experimental ==
 
=== Optimum uncoupler concentration ===
:::: A titration of an uncoupler is necessary to achive the optimum concentration necessary for maximum stimulation of noncoupled respiration ([[ET capacity]]) and to avoid inhibition of respiration by the too high uncoupler concentration. The underlying mechanism for the latter is not clear.
 
:::: Uncouplers must be titrated carefully up to an optimum concentration for maximum stimulation of flux, since excess concentrations of uncoupler exert a strongly inhibitory effect.
 
:::: See Steinlechner-Maran et al for a comparison of uncoupler titrations with [[FCCP]] and [[DNP]] from the [[ROUTINE state]] to the [[ET capacity|ET state]] of cell respiration. <ref> Steinlechner-Maran R, Eberl T, Kunc M, Margreiter R, Gnaiger E (1996) Oxygen dependence of respiration in coupled and uncoupled endothelial cells. Am J Physiol Cell Physiol 271:C2053-61. [[Steinlechner-Maran_1996_Am J Physiol Cell Physiol |»Bioblast link«]]</ref> Uncoupler titrations after inhibition of respiration by oligomycin in the [[coupling control protocol]] with intact cells yield the sequence of [[ROUTINE respiration]], [[LEAK respiration]] and [[ET capacity]], followed by inhibition to ROX. <ref>Hütter E, Renner K, Pfister G, Stöckl P, Jansen-Dürr P, Gnaiger E (2004) Senescence-associated changes in respiration and oxidative phosphorylation in primary human fibroblasts. Biochem J 380:919-28. [[Huetter_2004_Biochem J |»Bioblast link«]]</ref>,<ref>Gnaiger E (2008) Polarographic oxygen sensors, the oxygraph and high-resolution respirometry to assess mitochondrial function. In: Mitochondrial Dysfunction in Drug-Induced Toxicity (Dykens JA, Will Y, eds) John Wiley:327-52. [[Gnaiger_2008_POS |»Bioblast link«]]</ref> The highest accuracy of uncoupler titrations is achieved by titrations with the [[TIP2k]] at high concentrations of the stock solution. <ref>Gnaiger E (2008) Polarographic oxygen sensors, the oxygraph and high-resolution respirometry to assess mitochondrial function. In: Mitochondrial Dysfunction in Drug-Induced Toxicity (Dykens JA, Will Y, eds) John Wiley:327-52. [[Gnaiger_2008_POS |»Bioblast link«]]</ref> Increasing the concentration in small steps, most accurately titrated by the [[TIP2k]], is recommended (0.5 or 0.25 µM steps or even smaller).
 
:::: The optimum concentration of an uncoupler has to be determined for every biological system. It varies with incubation medium, sample concentratin, pharmacological treatment (with or without oligomycin), and pathophysiological state (e.g. induction of apoptosis). A single dose of uncoupler usually leads to an artefact in the estmation of maximum flux or Electron transfer-pathway capacity (for discussion, see [[Talk:Rogers_2011_PlosOne#Uncoupled_flux_does_not_reflect_electron_transfer_system_capacity|Artefacts by single dose uncoupling]]).
 
:::: The optimum uncoupler (CCCP, FCCP, DNP) concentration for the noncoupled state varies over a large concentration range, depending on the medium ('binding' of uncoupler), type and concentration of sample.  This is true for various uncouplers, such as CCCP, FCCP and DNP. <ref> Steinlechner-Maran R, Eberl T, Kunc M, Margreiter R, Gnaiger E (1996) Oxygen dependence of respiration in coupled and uncoupled endothelial cells. Am J Physiol Cell Physiol 271:C2053-61. [[Steinlechner-Maran_1996_Am J Physiol Cell Physiol |»Bioblast link«]]</ref>  To evaluate the optimum concentration, a uncoupler titration has to be performed initially. For subsequent application series, we recommend a few titrations starting close to optimum concentration. <ref>Hütter E, Renner K, Pfister G, Stöckl P, Jansen-Dürr P, Gnaiger E (2004) Senescence-associated changes in respiration and oxidative phosphorylation in primary human fibroblasts. Biochem J 380:919-28. [[Huetter_2004_Biochem J |»Bioblast link«]]</ref>,<ref>Pesta D, Gnaiger E (2012) High-resolution respirometry. OXPHOS protocols for human cells and permeabilized fibres from small biopisies of human muscle. Methods Mol Biol 810:25-58. [[Pesta 2012 Methods Mol Biol |»Bioblast link«]]</ref>  Optimum CCCP or FCCP concentrations range over an order of magnitude, from <0.5 to >4.0 µM.
 
=== Uncoupler titration ===
:::: In '''uncoupler titrations''' various [[uncoupler]]s, such as CCCP, FCCP or DNP <ref>Fontana-Ayoub M, Fasching M, Gnaiger E (2014) Selected media and chemicals for respirometry with mitochondrial preparations. Mitochondr Physiol Network 03.02(17):1-9. [[MiPNet03.02 Chemicals-Media |»Bioblast link«]]</ref> are applied to uncouple mitochondrial electron transfer through Complexes I to IV from phosphorylation (Complex V or ATP synthase, ANT and phosphate transport), particularly with the aim to obtain the noncoupled [[ET-state]] with an [[optimum uncoupler concentration]] at maximum [[oxygen flux]].
 
 
== Uncoupling control ratio, UCR ==
:::: Uncouplers may be used not only in isolated mitochondria or permeabilized tissue preparations, but also in intact cells.  Uncouplers are permeable through the cell membrane, and intact cells contain energy substrates for mitochondrial respiration.  The noncoupled (uncoupler-activated) state may be compared with [[ROUTINE respiration]] of the intact cells, in terms of the ''R/E'' or [[ROUTINE control ratio]] (compare: [[uncoupler control ratio]], UCR).  Or the non-coupled state may be the basis for evaluating [[LEAK respiration]] in the mitochondrial resting state induced by the addition of oligomycin (inhibitor of ATP synthase) or atractyloside (inhibitor of ANT), obtaing the ''L/E'' or LEAK control ratio (compare [[respiratory acceptor control ratio]], RCR).
 
:::: There are strong mathematical arguments to replace the conventional UCR and [[RCR]] by the corresponding [[flux control factor]]s <ref>Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. Int J Biochem Cell Biol 41:1837-45. [[Gnaiger 2009 Int J Biochem Cell Biol |»Bioblast link«]]</ref>,<ref> Gnaiger E. Biochemical coupling efficiency: from 0 to <1. Mitochondr Physiol Network. »[[ET-pathway coupling efficiency]]«</ref> and [[flux control ratio]]s.
 
{|border="1"
|1/UCR = [[ROUTINE respiration]] / Noncoupled respiration  =  ''R/E''; [[ROUTINE control ratio]]
|-
|Compare:  ''L/E''; [[LEAK control ratio]]
|-
|Compare: ''P/E''; [[OXPHOS control ratio]]
|}
 
 
:::: When using uncouplers in [[mitochondrial preparations]] (mt-preparations: isolated mitochondria and permeabilized tissue or cells), different applications are distinguished:
 
::::# External energy substrates have to be added to the preparation, since the endogenous substrates of the cytoplasm have been removed. A residual amount of internal mitochondrial substrates may be removed, if necessary, by an initial addition of a very small amount of ADP to the mitochondrial medium (e.g. [[MiR06]]) containing inorganic phosphate.
::::# In mt-preparations, an uncoupler may be added as a methodological test for plasma membrane permeabilization. If the inital addition of ADP does not exert a stimulatory effect, subsequent addition of uncoupler will increase respiratory flux if permeabilization has not been achieved.
::::# The classical respiratory control ratio ([[RCR]]=[[State 3]]/[[State 4]]) may be compared with an uncoupler-induced respiratory control ratio. Uncoupler titrations are initiated in a resting state, to induce an activated, noncoupled state. In the absence of [[adenylates]] (no ADP, ATP or AMP added), or in State 4 of isolated mitochondria (in the presence of ATP after phosphorylation of ADP), titration of uncoupler stimulates respiration. If [[OXPHOS]] has been initiated by the addition of a saturating concentration of ADP (which is different in isolated mitochondria versus permeabilized tissue or cell preparations), the experiment may be continued by addition of oligomycin or atractyloside, to return to a LEAK state, followed by uncoupler titration.
::::# Respiratory flux in the noncoupled state is compared with [[OXPHOS]] (saturating ADP in the coupled state), to evaluate metabolic flux control by the phosphorylation system over the electron transfer capacity. Importantly, flux control by the phosphorylation system depends on the combination of [[MitoPedia: Substrates and metabolites|substrates]] and [[MitoPedia: Inhibitors|inhibitors]] applied to activate various segments of the [[Electron transfer-pathway]], and varies in different states of [[Cytochrome_c_control_factor#Cytochrome c release|cytochrome ''c'' release]].
 
 
== References ==
<references/>
* http://www.bmb.leeds.ac.uk/illingworth/oxphos/poisons.htm


:::: »[[O2k-Publications: Coupling efficiency;uncoupling]]
:::: »[[O2k-Publications: Coupling efficiency;uncoupling]]
:::: »[[O2k-Publications: Instruments;methods]]




== Related MitoPedia pages ==
{{MitoPedia topics
::* '''Electron transfer-pathway, ET-pathway'''
|mitopedia topic=Uncoupler
::::» [[Electron transfer-pathway]]
::::» [[Q-junction]]
 
::* '''Electron transfer-pathway states'''
::::» [[Electron transfer-pathway state]]
 
::* '''Coupling control state ''E'''''
::::[[File:E.jpg |link=ET capacity]] [[ET capacity]]
::::» [[Noncoupled respiration]]
::::» [[Uncoupler#Is_respiration_uncoupled_-_noncoupled_-_dyscoupled.3F |Is respiration uncoupled - noncoupled - dyscoupled?]]
 
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Revision as of 14:25, 8 June 2020


high-resolution terminology - matching measurements at high-resolution


Uncoupler

Description

An uncoupler is a protonophore (CCCP, FCCP, DNP) which cycles across the inner mt-membrane with transport of protons and dissipation of the electrochemical proton gradient. Mild uncoupling may be induced at low uncoupler concentrations, the noncoupled state of ET capacity is obtained at optimum uncoupler concentration for maximum flux, whereas at higher concentrations an uncoupler-induced inhibition is observed.

Abbreviation: U

Reference: Noncoupled respiration

List of uncouplers

» MitoPedia: Uncouplers


Questions.jpg


Click to expand or collaps
Bioblast links: Uncoupling - >>>>>>> - Click on [Expand] or [Collapse] - >>>>>>>
Specific
» Artefacts by single dose uncoupling
» ATP synthase
» CCCP
» Coupling-control protocol
» DNP
» Dyscoupled respiration
» FCCP
» Is respiration uncoupled - noncoupled - dyscoupled?
» Noncoupled respiration: Discussion
» Uncoupler
» Uncoupled respiration - see » Noncoupled respiration
» Uncoupling proteins
» Uncoupling protein 1
» Uncoupler titrations - Optimum uncoupler concentration
Respiratory states and control ratios
» Biochemical coupling efficiency
» Coupling-control state
» Electron-transfer-pathway state
» Electron-transfer pathway
E.jpg ET capacity
» E-L coupling efficiency
» Flux control efficiency
» Flux control ratio
» LEAK-control ratio
» LEAK respiration
» Noncoupled respiration
» OXPHOS
» OXPHOS capacity; » State 3
» OXPHOS-control ratio, P/E ratio
» Respiratory acceptor control ratio
» ROUTINE-control ratio
» ROUTINE respiration
» ROUTINE state
» State 3u
» State 4
» Uncoupling-control ratio UCR
General (alphabetical order)
» Adenine nucleotide translocase
» Adenylates
» Electron transfer pathway
» Mitochondrial preparations
» mt-membrane potential
» Oxygen flux
» Phosphorylation system
» Proton leak
» Proton slip
» TIP2k
Other keyword lists
» Template:Keywords: Force and membrane potential



Questions.jpg


Click to expand or collaps
Bioblast links: Force and membrane potential - >>>>>>> - Click on [Expand] or [Collapse] - >>>>>>>
Fundamental relationships
» Force
» Affinity
» Flux
» Advancement
» Advancement per volume
» Stoichiometric number
mt-Membrane potential and protonmotive force
» Protonmotive force
» Mitochondrial membrane potential
» Chemical potential
» Faraday constant
» Format
» Uncoupler
O2k-Potentiometry
» O2k-Catalogue: O2k-TPP+ ISE-Module
» O2k-Manual: MiPNet15.03 O2k-MultiSensor-ISE
» TPP - O2k-Procedures: Tetraphenylphosphonium
» Specifications: MiPNet15.08 TPP electrode
» Poster
» Unspecific binding of TPP+
» TPP+ inhibitory effect
O2k-Fluorometry
» O2k-Catalogue: O2k-FluoRespirometer
» O2k-Manual: MiPNet22.11 O2k-FluoRespirometer manual
» Safranin - O2k-Procedures: MiPNet20.13 Safranin mt-membranepotential / Safranin
» TMRM - O2k-Procedures: TMRM
O2k-Publications
» O2k-Publications: mt-Membrane potential
» O2k-Publications: Coupling efficiency;uncoupling


»O2k-Publications: Coupling efficiency;uncoupling


MitoPedia topics: Uncoupler