Lysosomal Acidification Mechanisms *

Lysosomes are the terminal organelles on the endocytic pathway, digesting macromolecules and making their components available to the cell as nutrients. Hydrotlytic enzymes specific to a wide range of targets reside within the lysosome; these enzymes are activated by the highly acidic pH (between 4.5 and 5.0) in the organelles' interior. Lysosomes generate and maintain their pH gradients using the activity of a proton-pumping V-type ATPase, which uses metabolic energy in the form of ATP to pump protons into the lysosome lumen. Since this activity separates electric charge and generates a transmembrane voltage, another ion must move to dissipate this voltage for net pumping to occur. This so-called counterion may be either a cation (moving out of the lysosome) or an anion (moving in). Recent data supports the involvement of ClC-7, a Cl-/H+ antiporter in this process, though many open questions remain as to this transporter's involvement. Though functional results also point to a cation transporter, its molecular identity remains uncertain. Both the V-ATPase and the counterion transporter are likely to be important players in the mechanisms determining the steady state pH of the lysosome interior. Exciting new results suggest that lysosomal pH may be dynamically regulated in some cell types.