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Decrease, OXPHOS leads to Decreased Na/K ATPase activity
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of complex I of the electron transport chain leading to chemical induced Fanconi syndrome||adjacent||Not Specified||Not Specified||Marvin Martens (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
A decrease in oxidative phosphorylation results in a limited resource in ATP, which limits the capacity of the cell to perform active transport across the plasma membrane. This, in turn, reduces the capacity for secondary transport, resulting in different rates on water and solutes transport compared to healthy proximal tubule cells.
Evidence Supporting this KER
Both mitochondria and the Na/K ATPase are present in most cell types in mammals. Oxidative phosphorylation (OXPHOS) is the process by which the mitochondria produce most of the ATP used by the cell. In OXPHOS, the reducing equivalents (NADH and FADH2) produced during the catabolism of glucose and fatty acids fuel the electron transport chain (ETC) that provides the proton gradient needed ATP synthase to produce ATP from ADP and inorganic phosphate. This ATP can then be consumed by ATP-dependent processes such as the transport of sodium and potassium against their electrochemical gradients by the Na/K ATPase. When ATP levels are decreased in the cell, these ATP-dependent processes cannot take place. In the case of a decrease in Na/K ATPase activity, this results in a depolarisation of the plasma membrane, as well as a reduction in secondary active transport driven by the sodium gradient built up by the Na/K ATPase.
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Jørgensen, P. L. (1986). Structure, function and regulation of Na,K-ATPase in the kidney. Kidney International, 29(1), 10–20. https://doi.org/10.1038/KI.1986.3
Nowak, G. (2002). Protein kinase C-alpha and ERK1/2 mediate mitochondrial dysfunction, decreases in active Na+ transport, and cisplatin-induced apoptosis in renal cells. The Journal of Biological Chemistry, 277(45), 43377–88. https://doi.org/10.1074/jbc.M206373200
Yin, W., Li, X., Feng, S., Cheng, W., Tang, B., Shi, Y. L., & Hua, Z. C. (2009). Plasma membrane depolarization and Na,K-ATPase impairment induced by mitochondrial toxins augment leukemia cell apoptosis via a novel mitochondrial amplification mechanism. Biochemical Pharmacology, 78(2), 191–202.