Relationship: 1809
Title
Upstream event
Inhibition, NADH-ubiquinone oxidoreductase (complex I)Downstream event
Decrease, OXPHOS
Key Event Relationship Overview
AOPs Referencing Relationship
| 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
Sex Applicability
Life Stage Applicability
Key Event Relationship Description
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
Biological Plausibility
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
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)
Quantitative Understanding of the Linkage
Domain of Applicability
References
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