Modulation of Potassium Ion Transport in Mitochondria by Kaempferol and Its Glycosides
DOI:
https://doi.org/10.48048/tis.2026.13296Keywords:
Liver mitochondria, mitoKATP, ATP, Mg2 , valinomycin, kaempferol and its glycosidesAbstract
Several types of potassium channels are embedded in the inner mitochondrial membrane and play a crucial role in cellular function. Among them, the ATP-sensitive potassium channel located in the mitochondrial inner membrane (mitoKATP) is known to protect organs and tissues from ischemia-reperfusion injury. In recent years, increasing attention has been devoted to investigating the effects of flavonoids-widely distributed plant-derived secondary metabolites-on various physiopathological processes occurring in the organism. Accordingly, the present study examined the effects of kaempferol and its glycosides isolated from Geranium rotundifolium on mitochondrial ATP-sensitive potassium channel activity in an ATP- and Mg2+-dependent manner, as well as their influence on K+ ion transport. At a constant ATP concentration of 200 μM, kaempferol and its glycosides activated mitoKATP activity in a dose-dependent manner, with their effectiveness decreasing in the following order: kaempferol > kaempferitrin > kaempferol-7-O-rhamnoside > afzelin. At lower ATP concentrations, kaempferol induced weaker channel activation; however, increasing ATP levels enhanced the degree of mitoKATP activation by kaempferol. Simultaneously, increasing the concentration of Mg2+ ions resulted in a reduction of kaempferol-induced mitoKATP activation. In the presence of the K+ ionophore valinomycin, kaempferol more effectively counteracted the succinate-driven reverse K+ influx into the mitochondrial matrix compared to other flavonoids. To gain mechanistic insight at the molecular level, in silico docking analysis was performed using the human mitochondrial ATP-binding cassette transporter ABCB8. The docking results revealed stable binding of kaempferol and its glycosides within the ligand-recognition cavity of ABCB8, with binding energies ranging from –6.9 to –8.8 kcal/mol, and indicated a higher affinity of glycosylated flavonoids compared to the aglycone. These interactions were stabilized by hydrogen bonding and hydrophobic contacts with key transmembrane residues, suggesting a potential modulatory role of flavonoids on mitochondrial transport processes. In conclusion, kaempferol and its glycosides may provide protective effects against ischemia-reperfusion injury in the liver and other organs under various stress conditions by modulating the activity of mitoKATP and regulating K+ ion transport.
HIGHLIGHTS
- The activity of the mitoKATP channel in the presence of kaempferol and its glycosides was investigated. It was found that these flavonoids increase mitoKATP channel activity in a dose-dependent manner under conditions where Mg2+ and ATP are present.
- In the presence of the K+ ionophore valinomycin, kaempferol more effectively counteracted the succinate-driven reverse K+ influx into the mitochondrial matrix compared to other flavonoids.
- Docking simulations revealed stable binding of afzelin, kaempferol, kaempferitrin, and kaempferol-7-O-rhamnoside within the ligand-recognition cavity of ABCB8, with binding energies ranging from –6.9 to –8.8 kcal/mol.
- This indicates that kaempferol and its glycosides, by interacting with the mitoKATP channel, protect against ischemia-reperfusion, at that restore mitochondrial and cellular function.
GRAPHICAL ABSTRACT
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