Sodium ion (Na+) levels need to be carefully regulated, which relies on ion channels and transporters that are present in the plasma membrane and organelle membranes, to ensure normal physiology and ion homeostasis. The measurement of organellar Na+ levels is difficult owing to the acidic nature of organelle lumens. To overcome the pH dependence, Zou et al. have developed a pH-insensitive Na+ reporter (termed RatiNa) that enables ratiometric measurements of Na+ in organelles. RatiNa is a three-stranded DNA nanodevice in which one strand carries a pH-insensitive fluorophore known as ChicagoGreen; another bears an ion-insensitive internal reference dye to enable ratiometry; and a third helps to target RatiNa to organelles. When cells are incubated with RatiNa, it is ferried to endocytic organelle lumens via receptor-mediated endocytosis. The team could thereby map Na+ in organelles of cultured macrophages and in coelomocytes of Caenorhabditis elegans. Zou et al. found that early endosomes had high luminal Na+ levels that decreased progressively with endosomal maturation, unlike observations in previous studies of ions such as Ca2+, Cl− and H+. RatiNa could capture, in live cells, the activity of organelle-resident Na+-transporting proteins such as TPC2 (a lysosomal Na+ channel) or NHE6 (a lysosomal Na+/H+ exchanger). RatiNa revealed that salt stress in C. elegans massively depleted Na+ specifically in lysosomes, which suggests that lysosomes help cells to counteract salt stress. Overall, RatiNa offers a unique opportunity to visualize Na+ changes in intact cells and organisms at subcellular resolution, with high specificity and precision.
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