Bioimaging revealed contrasting organelle-specific transport of copper and zinc and implication for toxicity

Zn and Cu are two of the essential trace elements and it is important to understand the regulation of their distribution on cellular functions. Herein, we for the first time investigated the subcellular fate and behavior of Zn and Cu in zebrafish cells through bioimaging, and demonstrated the completely different behaviors of Zn and Cu. The distribution of Zn2+ was concentration-dependent, and Zn2+ at low concentration was predominantly located in the lysosomes (76.5%). A further increase of cellular Zn2+ resulted in a spillover and more diffusive distribution, with partitioning to mitochondria and other regions. In contrast, the subcellular distribution of Cu+ was time-dependent. Upon entering the cells, Cu2+ was reduced to Cu+, which was first concentrated in the mitochondria (71.4%) followed by transportation to lysosomes (58.6%), and finally removal from the cell. With such differential transportation, Cu2+ instead of Zn2+ had a negative effect on the mitochondrial membrane potential and glutathione. Correspondingly, the pH of lysosomes was more sensitive to Zn2+ exposure and decreased with increasing internalized Zn2+, whereas it increased upon Cu2+ exposure. The responses of cellular pH showed an opposite pattern from the lysosomal pH. Lysosome was the most critical organelle in response to incoming Zn2+ by increasing its number and size, whereas Cu2+ reduced the lysosome size. Our study showed that Zn2+ and Cu2+ had completely different cellular handlings and fates with important implications for understanding of their toxicity.