2.B.120.  The α-Aminooxy Acid-based K⁺/H⁺ Exchanger (AAA-K+/H+E) Family 

Shen et al. 2020 studied an α-aminooxy acid-based K⁺/H⁺ exchanger 2. Molecule 2 undergoes deprotonation at pH 8.0 outside the vesicle and forms a neutral complex with a potassium ion. Upon diffusion into the intravesicular region at pH 6.8, K⁺/H⁺ exchange takes place to re-protonate 2, which then returns to the outside of the vesicle in a protonated form to complete the K⁺/H⁺ exchange cycle (Yuan et al. 2024). In the lipid bilayer system, 2 exhibits remarkable selectivity for potassium ions, with an EC₅₀(K⁺)/EC₅₀(Na⁺) ratio of 23.4 and a R_K⁺/R_Na⁺ value of 16.0. Moreover, the molecule utilizes the pH gradient present in the mitochondria and lysosomes as a driving force for the selective transmembrane transport of K⁺/H⁺ across these organelles’ membranes. The transport of K⁺/H⁺ disrupts mitochondrial function, resulting in the dissipation of the membrane potential, elevated ROS production, and the initiation of apoptosis. Additionally, the lysosomal-mediated H⁺ efflux raises lysosome alkalinity and inhibits late protein degradation, consequently suppressing autophagy. By inducing apoptosis and inhibiting autophagy, 2 selectively eliminates drug-resistant ovarian cancer stem cells, exhibiting cytotoxicity up to 47 times higher than that observed in conventional cancer cells. This and other K⁺ ionophores have been reviewed (Yuan et al. 2024). The transport of K⁺/H⁺ disrupts mitochondrial function, resulting in the dissipation of the membrane potential, elevated ROS production, and the initiation of apoptosis. Additionally, lysosomal-mediated H⁺ efflux raises lysosome alkalinity and inhibits late protein degradation, consequently suppressing autophagy. By inducing apoptosis and inhibiting autophagy, 2 selectively eliminates drug-resistant ovarian cancer stem cells, exhibiting cytotoxicity up to 47 times higher than that observed in conventional cancer cells.

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