Lysosome-Related Organelles in Intestinal Cells Are a Zinc Storage Site in C. elegans

Abstract

SUMMARY Zinc is an essential trace element involved in many biological processes and human diseases. Because zinc deficiency and excess are deleterious, animals require homeostatic mechanisms to maintain zinc levels in response to dietary fluctuations. Here we demonstrate that lysosome-related organelles in intestinal cells of C. elegans, called gut granules, function as the major site of zinc storage. Zinc storage in gut granules promotes detoxification and subsequent mobilization, linking cellular and organismal zinc metabolism. The cation diffusion facilitator protein CDF-2 plays a critical role in this process by transporting zinc into gut granules. In response to high dietary zinc, gut granules displayed structural changes characterized by a bilobed morphology with asymmetric distributions of zinc and molecular markers. We defined a genetic pathway that mediates the formation of bilobed morphology. These findings elucidate mechanisms of zinc storage, detoxification and mobilization in C. elegans and may be relevant to other animals.

The Intestinal Copper Exporter CUA-1 Is Required for Systemic Copper Homeostasis in Caenorhabditis elegans

“…Consistent with previous reports, pgp-2 mutant worms displayed lower zinc content independent of copper supplementation (supplemental Fig. S7, A and B) (8). These results indicate that copper deposition accounts for a significant proportion of total body copper in C. elegans and that gut granules are at least partially required for copper detoxification.…”

“…We used the Rhodol-based CF4 probe and control CF4 probe (both final concentrations of 25 M) for staining copper(I) in intact worms and 2 M LysoTracker Red DND-99 (Invitrogen) for detecting gut granules. Both chemicals were prepared in M9 buffer and dispensed onto NGM plates (8). L3 stage worms were cultured on these dishes for 12-16 h in the dark.…”

“…For these reasons, we utilized C. elegans, which has been widely used in the study of the metabolism of other metals, including iron, heme, and zinc (8,(13)(14)(15)(16)(17). Although mammals have two copper exporters, serving complementary functions in different tissues such as the gut and liver, lower metazoans (including nematodes (C. elegans) and insects (Drosophila melanogaster)) have only a single homolog of ATP7A/B (2,18,19).…”

“…Although the optically transparent roundworm Caenorhabditis elegans has emerged as a highly amenable model of micronutrient metabolism (7)(8)(9), the C. elegans model system has been relatively unexploited for questions related to copper homeostasis, despite the fact that these worms have a defined and highly versatile intestinal capacity for nutrient absorption (10 -12). For these reasons, we utilized C. elegans, which has been widely used in the study of the metabolism of other metals, including iron, heme, and zinc (8,(13)(14)(15)(16)(17).…”

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

“…The regulatory function similar to CDF1 is conducted by SUR-7 (no vertebrate ZnT homologs), which is probably localized to the ER. In homeostatic control, CDF2 (a ZnT2 homolog) or TTM-1 (no vertebrate ZnT homologs) also plays a crucial role by transporting zinc into gut granules (lysosome-related organelles) or excreting zinc from the apical plasma membrane in intestinal cells, respectively (348,349).…”