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Decrease, Coupling of OXPHOS leads to Decrease, ATP pool
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Uncoupling of oxidative phosphorylation leading to growth inhibition via decreased cell proliferation||adjacent||High||High||You Song (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|Uncoupling of oxidative phosphorylation leading to growth inhibition via ATP depletion associated cell death||adjacent||Moderate||Not Specified||You Song (send email)||Open for citation & comment||Under Development|
|Uncoupling of oxidative phosphorylation leading to growth inhibition via decreased Na-K ATPase activity||adjacent||You Song (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
This key event relationship describes the dissipation of protonmotive force across the inner mitochondrial membrane by uncouplers (uncoupling of oxidative phosphorylation), leading to reduced total adenosine triphosphate (ATP) pool in cells or organisms.
Evidence Collection Strategy
Evidence Supporting this KER
The overall evidence supporting Relationship 2203 is considered high.
The biological plausibility of Relationship 2203 is considered high.
Rationale: In eukaryotic cells, the major metabolic pathways responsible for ATP production are OXPHOS, citric acid (TCA) cycle, glycolysis and photosynthesis. Oxidative phosphorylation is much (theoretically 15-18 times) more efficient than the rest due to high energy derived from oxygen during aerobic respiration (Schmidt-Rohr 2020). As the ATP level is relatively balanced between production and consumption (Bonora 2012), ATP depletion is a plausible consequence of reduced ATP synthetic efficiency following uncoupling of OXPHOS.
Uncertainties and Inconsistencies
- A significant decrease followed by a significant increase in total ATP was observed in human RD cells during a 48h exposure to the uncoupler FCCP (Kuruvilla 2003), possibly due to the enhancement of other ATP synthetic pathways (e.g., glycolysis) as a compensatory action to impaired OXPHOS (Jose 2011
Known modulating factors
A regression based quantitative response-response relationship between uncoupling of OXPHOS and ATP depletion was proposed for the crustacean Daphnia magna under UVB stress (Song 2020).
Known Feedforward/Feedback loops influencing this KER
- It is known that mild uncoupling of oxidative phosphorylation can enhance the activity of the mitochondrial electron transport chain to produce more ATP, and/or activate other ATP synthetic pathways (e.g., glycolysis) as a compensatory action to impaired OXPHOS (Jose 2011).
Domain of Applicability
Relationship 2203 is considered applicable to eukaryotes, as mitochondrial oxidative phosphorylation and ATP synthesis are highly conserved in these organisms. Uncoupling of oxidative phosphorylation leading to ATP depletion is a well-documented relationship in many taxa, such as human, rodents and fish.
Relationship 2203 is considered applicable to all genders, as mitochondrial oxidative phosphorylation and ATP synthesis are fundamental biological processes and are not sex-pecific.
Relationship 2203 is considered applicable to all life-stages, as mitochondrial oxidative phosphorylation and ATP synthesis are essential energy production processes for maintaining basic biological activities.
Beard DA. 2005. A biophysical model of the mitochondrial respiratory system and oxidative phosphorylation. PLOS Computational Biology 1:e36. DOI: 10.1371/journal.pcbi.0010036.
Bestman JE, Stackley KD, Rahn JJ, Williamson TJ, Chan SS. 2015. The cellular and molecular progression of mitochondrial dysfunction induced by 2,4-dinitrophenol in developing zebrafish embryos. Differentiation 89:51-69. DOI: 10.1016/j.diff.2015.01.001.
Bonora M, Patergnani S, Rimessi A, De Marchi E, Suski JM, Bononi A, Giorgi C, Marchi S, Missiroli S, Poletti F, Wieckowski MR, Pinton P. 2012. ATP synthesis and storage. Purinergic Signalling 8:343-357. DOI: 10.1007/s11302-012-9305-8.
Heiske M, Letellier T, Klipp E. 2017. Comprehensive mathematical model of oxidative phosphorylation valid for physiological and pathological conditions. The FEBS Journal 284:2802-2828. DOI: https://doi.org/10.1111/febs.14151.
Jose C, Bellance N, Rossignol R. 2011. Choosing between glycolysis and oxidative phosphorylation: A tumor's dilemma? Biochimica et Biophysica Acta (BBA) - Bioenergetics 1807:552-561. DOI: https://doi.org/10.1016/j.bbabio.2010.10.012.
Koczor CA, Shokolenko IN, Boyd AK, Balk SP, Wilson GL, Ledoux SP. 2009. Mitochondrial DNA damage initiates a cell cycle arrest by a Chk2-associated mechanism in mammalian cells. J Biol Chem 284:36191-36201. DOI: 10.1074/jbc.M109.036020.
Kubo S, Niina T, Takada S. 2020. Molecular dynamics simulation of proton-transfer coupled rotations in ATP synthase FO motor. Scientific Reports 10:8225. DOI: 10.1038/s41598-020-65004-1.
Kuruvilla S, Qualls CW, Jr., Tyler RD, Witherspoon SM, Benavides GR, Yoon LW, Dold K, Brown RH, Sangiah S, Morgan KT. 2003. Effects of minimally toxic levels of carbonyl cyanide P-(trifluoromethoxy) phenylhydrazone (FCCP), elucidated through differential gene expression with biochemical and morphological correlations. Toxicol Sci 73:348-361. DOI: 10.1093/toxsci/kfg084.
Luz AT, Godebo TR, Bhatt DP, Ilkayeva OR, Maurer LL, Hirschey MD, Meyer JN. 2016. Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-Like Effect in Caenorhabditis elegans. Toxicol Sci 154:195-195. DOI: 10.1093/toxsci/kfw185.
Schmidt-Rohr K. 2020. Oxygen is the high-energy molecule powering complex multicellular life: fundamental corrections to traditional bioenergetics. ACS Omega 5:2221-2233. DOI: 10.1021/acsomega.9b03352.
Schmitz JPJ, Vanlier J, van Riel NAW, Jeneson JAL. 2011. Computational modeling of mitochondrial energy transduction. 39:363-377. DOI: 10.1615/CritRevBiomedEng.v39.i5.20.
Shim J, Weatherly LM, Luc RH, Dorman MT, Neilson A, Ng R, Kim CH, Millard PJ, Gosse JA. 2016. Triclosan is a mitochondrial uncoupler in live zebrafish. J Appl Toxicol 36:1662-1667. DOI: 10.1002/jat.3311.
Sithara T, Arun KB, Syama HP, Reshmitha TR, Nisha P. 2017. Morin inhibits proliferation of SW480 colorectal cancer cells by inducing apoptosis mediated by reactive oxygen species formation and uncoupling of Warburg effect. Frontiers in Pharmacology 8. DOI: 10.3389/fphar.2017.00640.
Song Y, Xie L, Lee Y, Tollefsen KE. 2020. De novo development of a quantitative adverse outcome pathway (qAOP) network for ultraviolet B (UVB) radiation using targeted laboratory tests and automated data mining. Environmental Science & Technology 54:13147-13156. DOI: 10.1021/acs.est.0c03794.
Sweet S, Singh G. 1999. Changes in mitochondrial mass, membrane potential, and cellular adenosine triphosphate content during the cell cycle of human leukemic (HL-60) cells. Journal of Cellular Physiology 180:91-96. DOI: https://doi.org/10.1002/(SICI)1097-4652(199907)180:1<91::AID-JCP10>3.0.CO;2-6.
Weatherly LM, Nelson AJ, Shim J, Riitano AM, Gerson ED, Hart AJ, de Juan-Sanz J, Ryan TA, Sher R, Hess ST, Gosse JA. 2018. Antimicrobial agent triclosan disrupts mitochondrial structure, revealed by super-resolution microscopy, and inhibits mast cell signaling via calcium modulation. Toxicol Appl Pharmacol 349:39-54. DOI: 10.1016/j.taap.2018.04.005.
Weatherly LM, Shim J, Hashmi HN, Kennedy RH, Hess ST, Gosse JA. 2016. Antimicrobial agent triclosan is a proton ionophore uncoupler of mitochondria in living rat and human mast cells and in primary human keratinocytes. Journal of Applied Toxicology 36:777-789. DOI: https://doi.org/10.1002/jat.3209.