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Key Event Title
Decrease, Coupling of oxidative phosphorylation
|Level of Biological Organization|
Key Event Components
|oxidative phosphorylation uncoupler activity||mitochondrion||increased|
|regulation of mitochondrial membrane potential||mitochondrion||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Uncoupling of OXPHOS leading to growth inhibition 5||MolecularInitiatingEvent||You Song (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Uncoupling of OXPHOS leading to growth inhibition 1||MolecularInitiatingEvent||You Song (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|Uncoupling of OXPHOS leading to growth inhibition 2||MolecularInitiatingEvent||You Song (send email)||Open for citation & comment||Under Development|
|Uncoupling of OXPHOS leading to growth inhibition 3||MolecularInitiatingEvent||You Song (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Uncoupling of OXPHOS leading to growth inhibition 4||MolecularInitiatingEvent||You Song (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Uncoupling of OXPHOS leading to growth inhibition 6||MolecularInitiatingEvent||You Song (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Adult, reproductively mature||Moderate|
Key Event Description
Decreased coupling of oxidative phosphorylation (OXPHOS), or uncoupling of OXPHOS, describes dissipation of protonmotive force (PMF) across the inner mitochondrial membrane (IMM) by environmental stressors. In eukaryotes, the mitochondrial electron transport chain mediates a series of redox reactions to create a PMF across the IMM. The PMF is used as energy to drive adenosine triphosphate (ATP) synthesis through phosphorylation of adenosine diphosphate (ADP). These processes are coupled and referred to as OXPHOS. A number of chemicals can dissipate the PMF, leading to uncoupling of OXPHOS. This key event describes the main outcome of the interactions between an uncoupler and the transmembrane PMF. An uncoupler can bind to a proton in the mitochondrial inter membrane space, transport the proton to the matrix side of the IMM, release the proton and move back to the inter membrane space. These processes are repeated until the transmembrane PMF is dissipated. This KE is therefore a lumped term of these processes and represents the final consequence of the interactions.
How It Is Measured or Detected
Uncoupling of oxidative phosphorylation can be indicated by reduced mitochondrial membrane potential, increased proton leak and/or increased oxygen consumption rate.
- Mitochondrial membrane potential can be determined using ToxCast high-throughput screening bioassays such as “APR_HepG2_MitoMembPot”, “APR_Hepat_MitoFxnI”, and “APR_Mitochondrial_membrane_potential”, and the Tox21 high-throughput screening assay “tox21-mitotox-p1”.
- Mitochondrial membrane potential can also be measured using commercially available fluorescent probes such as TMRM (tetramethylrhodamine, methyl ester, perchlorate), TMRE (tetramethylrhodamine, ethyl ester, perchlorate) and JC-1 (Perry 2011).
- Proton leak and oxygen consumption rate can be measured using a high-resolution respirometry (Affourtit 2018) or a Seahorse XF analyzer (Divakaruni 2014).
Domain of Applicability
Taxonomic applicability domain
This key event is in general considered applicable to most eukaryotes, as the mitochondrion and oxidative phosphorylation are highly conserved (Roger 2017).
Life stage applicability domain
This key event is considered applicable to all life stages, as ATP synthesis by oxidative phosphorylation is an essential biological process for most living organisms.
Sex applicability domain
This key event is considered sex-unspecific, as both males and females use oxidative phosphorylation as a main process to generate ATP.
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Attene-Ramos MS, Huang R, Sakamuru S, Witt KL, Beeson GC, Shou L, Schnellmann RG, Beeson CC, Tice RR, Austin CP, Xia M. 2013. Systematic study of mitochondrial toxicity of environmental chemicals using quantitative high throughput screening. Chemical Research in Toxicology 26:1323-1332. DOI: 10.1021/tx4001754.
Attene-Ramos MS, Huang RL, Michael S, Witt KL, Richard A, Tice RR, Simeonov A, Austin CP, Xia MH. 2015. Profiling of the Tox21 chemical collection for mitochondrial function to identify compounds that acutely decrease mitochondrial membrane potential. Environ Health Persp 123:49-56. DOI: 10.1289/ehp.1408642.
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Sugiyama Y, Shudo T, Hosokawa S, Watanabe A, Nakano M, Kakizuka A. 2019. Emodin, as a mitochondrial uncoupler, induces strong decreases in adenosine triphosphate (ATP) levels and proliferation of B16F10 cells, owing to their poor glycolytic reserve. Genes to Cells 24:569-584. DOI: https://doi.org/10.1111/gtc.12712.
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