The role of calcium and other ions in sorting and delivery in the late endocytic pathway

The passage of endocytosed receptor-bound ligands and membrane proteins through the endocytic pathway of mammalian cells to lysosomes occurs via early and late endosomes. The latter contain many luminal vesicles and are often referred to as MVBs (multivesicular bodies). The overall morphology of endosomal compartments is, in major part, a consequence of the many fusion events occurring in the endocytic pathway. Kissing events and direct fusion between late endosomes and lysosomes provide a means of delivery to lysosomes. The luminal ionic composition of organelles in the endocytic pathway is of considerable importance both in the trafficking of endocytosed ligands and in the membrane fusion events. In particular, H⁺ ions play a role in sorting processes and providing an appropriate environment for the action of lysosomal acid hydrolases. Na⁺/H⁺ exchangers in the endosomal membrane have been implicated in the formation of MVBs and sorting into luminal vesicles. Ca²⁺ ions are required for fusion events and luminal content condensation in the lysosome. Consistent with an important role for luminal Ca²⁺ in traffic through the late endocytic pathway, mutations in the gene encoding mucolipin-1, a lysosomal non-specific cation channel, result in abnormalities in lipid traffic and are associated with the autosomal recessive lysosomal storage disease MLIV (mucolipidosis type IV).