Lysosomal Expansion Compartments Mediate Zinc and Copper Homeostasis in Caenorhabditis elegans

Abstract Zinc is an essential transition metal that participates in many biological processes. In C. elegans, excess zinc is stored in lysosomes in intestinal cells; this process involves increasing the expression of the zinc transporter CDF-2 and remodeling of lysosomes characterized by an increase in the volume of the expansion compartment. To determine if this is a more general property, we investigated other metals. Here we report that lysosomes are remodeled in response to excess copper, manganese, and cadmium, with each metal causing an increase in the volume of the expansion compartment. Mutants with a reduced number of lysosomes were hypersensitive to growth retardation caused by excess copper and manganese, suggesting metal toxicity is prevented by metal sequestration in lysosomes. We developed a method to analyze isolated lysosomes by X-ray Fluorescence Microscopy; zinc, copper, and manganese are detectable in the lumen of lysosomes, and the concentration of zinc in the lysosomes increased substantially in worms exposed to excess dietary zinc. To further analyze copper, we examined localization of CUA-1.1, a copper transporter that moves copper into the lumen of lysosomes. Like the zinc transporter CDF-2, CUA-1.1 localizes to both the acidified and expansion compartments in excess copper. These results indicate that the same intestinal lysosomes store both zinc and copper. Furthermore, lysosome remodeling characterized by an increase in volume of the expansion compartment is not specific to excess zinc but is a more general phenomenon during metal storage in lysosomes.