Zinc and manganese homeostasis closely interact in mammalian cells

Understanding the homeostatic interactions among essential trace metals is important for explaining their roles in cellular systems. Recent studies in vertebrates suggest that cellular Mn metabolism is related to Zn metabolism in multifarious cellular processes. However, the underlying mechanism remains unclear. In this study, we examined the changes in the expression of proteins involved in cellular Zn and/or Mn homeostatic control and measured the Mn as well as Zn contents and Zn enzyme activities to elucidate the effects of Mn and Zn homeostasis on each other. Mn treatment decreased the expression of the Zn homeostatic proteins metallothionein (MT) and ZNT1 and reduced Zn enzyme activities, which were attributed to the decreased Zn content. Moreover, loss of Mn efflux transport protein decreased MT and ZNT1 expression and Zn enzyme activity without changing extracellular Mn content. This reduction was not observed when supplementing with the same Cu concentrations and in cells lacking Cu efflux proteins. Furthermore, cellular Zn homeostasis was oppositely regulated in cells expressing Zn and Mn importer ZIP8, depending on whether Zn or Mn concentration was elevated in the extracellular milieu. Our results provide novel insights into the intricate interactions between Mn and Zn homeostasis in mammalian cells and facilitate our understanding of the physiopathology of Mn, which may lead to the development of treatment strategies for Mn‐related diseases in the future. This graphical illustrates our study's focus on Mn and Zn homeostatic control in mammalian cells. An increase in cellular Mn decreased the expression of Zn homeostatic proteins, including metallothionein and ZNT1, indicating decreased cellular Zn. In contrast, increased cellular Zn increased the expression of Mn homeostatic protein TMEM165, indicating decreased cellular Mn. These results indicate that Zn and Mn inversely interact with each other and that intracellular Mn and Zn homeostasis closely interact in mammalian cells.