API

Relationship: 1809

Title

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Inhibition, NADH-ubiquinone oxidoreductase (complex I) leads to Decrease, OXPHOS

Upstream event

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Inhibition, NADH-ubiquinone oxidoreductase (complex I)

Downstream event

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Decrease, OXPHOS

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Inhibition of complex I of the electron transport chain leading to chemical induced Fanconi syndrome adjacent Not Specified Not Specified

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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Inhibition of complex I activity leads to a drop in the electrochemical gradient across the inner mitochondrial membrane (mitochondrial membrane potential Δψm + proton gradient ΔpHm). This results in a decreased activity of ATP synthase and subsequent reduced levels of intracellular ATP.

Evidence Supporting this KER

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Biological Plausibility

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Complex I contributes one-third of the proton gradient needed for the activity of ATP synthase. Complexes II and III can function without complex I being active. However, Complex I inhibition also often causes an increase in reactive oxygen species, which can fragilize the electron transport chain and the mitochondrion in general (Lambert & Brand, 2004). Depending on the severity of complex I inhibition and its consequences, the ETC can be partially or totally blocked.

Empirical Evidence

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Complex I inhibitors such as rotenone and fenpyroximate have been shown to alter mitochondrial morphology and cause a concentration-dependent decrease in intracellular ATP levels in SH-SY5Y cells (Chen et al., 2017)

Uncertainties and Inconsistencies

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Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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References

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Chen, T., Tan, J., Wan, Z., Zou, Y., Afewerky, H. K., Zhang, Z., & Zhang, T. (2017). Effects of Commonly Used Pesticides in China on the Mitochondria and Ubiquitin-Proteasome System in Parkinson’s Disease. International Journal of Molecular Sciences, 18(12), 2507. https://doi.org/10.3390/ijms18122507

Lambert, A. J., & Brand, M. D. (2004). Inhibitors of the Quinone-binding Site Allow Rapid Superoxide Production from Mitochondrial NADH:Ubiquinone Oxidoreductase (Complex I). Journal of Biological Chemistry, 279(38), 39414–39420. https://doi.org/10.1074/jbc.M406576200