Zinc transporter ZIP13 in mesenchymal tissues: From intracellular metal distribution to systemic homeostasis.

BACKGROUND: Zinc is an essential trace element that plays pivotal roles in development, immunity, inflammation, and aging. Precise regulation of intracellular zinc distribution is mediated by zinc transporters of the ZIP (SLC39) and ZnT (SLC30) families, and their functions are increasingly recognized as tissue- and organelle-specific. Among these transporters, ZIP13 (SLC39A13) is a key regulator of mesenchymal biology. Genetic studies have demonstrated that loss of ZIP13 function causes connective tissue abnormalities, impaired bone and tooth development, and spondylodysplastic Ehlers-Danlos syndrome Type 3 in humans.

HIGHLIGHT: ZIP13 is predominantly localized to the Golgi apparatus, where it regulates metal homeostasis and modulates zinc-dependent signalling pathways, including transforming growth factor beta and bone morphogenic protein signalling. Recent studies have expanded the functional landscape of ZIP13 beyond connective tissues, demonstrating its involvement in adipose tissue biology, skeletal muscle maintenance, cardiac homeostasis, and stem cell differentiation. In addition, patient-derived induced pluripotent stem cell models have provided new insights into ZIP13-dependent mesenchymal differentiation and regenerative biology. Emerging evidence indicates that ZIP13 can transport not only zinc but also iron, suggesting that ZIP13 functions as a metal distributor that regulates intracellular metal allocation in a context-dependent manner.

CONCLUSION: The findings in this review support the concept that ZIP13-mediated metal homeostasis is indispensable for mesenchymal development, aging, and disease. By integrating evidence from animal models, human genetic disorders, and stem-cell-based studies, this review highlights the implications of ZIP13 biology in oral and systemic health, and it underscores the importance of intracellular metal allocation in development and regenerative medicine.