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Decrease, ATP pool leads to Decrease, Cell proliferation
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||Moderate||Moderate||You Song (send email)||Open for comment. Do not cite||Under Development|
|Mitochondrial ATP synthase antagonism leading to growth inhibition (1)||adjacent||You Song (send email)||Under development: Not open for comment. Do not cite|
|Mitochondrial complex III antagonism leading to growth inhibition (1)||adjacent||You Song (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
This key event relationship describes reduced adenosine triphosphate (ATP) supply leading to reduced cell proliferation (cell growth, division or a combination of these).
Evidence Supporting this KER
The overall evidence supporting Relationship 2204 is considered moderate.
The biological plausibility of Relationship 2204 is considered high.
Rationale: Cell proliferation is a well-known ATP-dependent process. Cell division processes, such as the mitotic cell cycle uses ATP for chromosome movements and DNA replication (Kingston 1999). The synthetic processes of major cellular components that are necessary for cell structure and growth, such as proteins and lipids, also require sufficient ATP supply (Bonora 2012). Depletion of ATP therefore has a negative impact on these processes.
Uncertainties and Inconsistencies
There are currently no inconsistencies based on the supporting literature.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Relationship 2204 is considered applicable to all eukaryotes, as ATP and cell proliferation are known to be tightly coupled in animals, plants and some microorganisms.
Relationship 2204 is considered applicable to all sexes, as ATP-dependent cell proliferation are used by both males and females in eukaryotes.
Relationship 2204 is considered applicable to all life stages, as ATP-dependent cell proliferation is an essential process for an organism throughout the entire life.
Ahmann FR, Garewal HS, Schifman R, Celniker A, Rodney S. 1987. Intracellular adenosine triphosphate as a measure of human tumor cell viability and drug modulated growth. In Vitro Cellular & Developmental Biology 23:474-480. DOI: 10.1007/BF02628417.
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.
Crouch SPM, Kozlowski R, Slater KJ, Fletcher J. 1993. The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity. Journal of Immunological Methods 160:81-88. DOI: https://doi.org/10.1016/0022-1759(93)90011-U.
Kingston RE, Narlikar GJ. 1999. ATP-dependent remodeling and acetylation as regulators of chromatin fluidity. Genes Dev 13:2339-2352. DOI: 10.1101/gad.13.18.2339.
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.
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.
Nieminen AL, Saylor AK, Herman B, Lemasters JJ. 1994. ATP depletion rather than mitochondrial depolarization mediates hepatocyte killing after metabolic inhibition. Am J Physiol 267:C67-74. DOI: 10.1152/ajpcell.1994.267.1.C67.
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.