Zinc as a master regulator of intracellular organelle homeostasis

Zinc (Zn²⁺) is an essential trace element that supports a vast array of cellular processes, including enzymatic catalysis, gene expression, immune regulation and signaling. Its unique redox-inert properties and ability to bind diverse proteins make it indispensable for cellular homeostasis. Zinc is dynamically distributed within cells, where its compartmentalization across organelles, such as the nucleus, endoplasmic reticulum, Golgi apparatus, mitochondria, lysosomes, endosomes and peroxisomes, enables specialized functions crucial for organelle integrity and interorganelle communication. The present Review provides a comprehensive account of organelle-specific zinc homeostasis, highlighting the intricate roles of zinc transporters, metallothioneins and metallochaperones in regulating zinc flux and buffering. Here we discuss how zinc modulates structural and enzymatic processes, stress responses, redox balance and signaling pathways within each organelle. We then provide an integrated overview of how its dysregulation contributes to diverse molecular dysfunctions and pathologies including neurodegeneration, cancer, metabolic disorders and aging. We further examine emerging therapeutic strategies aimed at restoring zinc homeostasis, including supplementation and bioengineered, organelle-targeted delivery systems, as well as advanced tools for visualizing zinc dynamics at subcellular resolution. Together, these insights demonstrate the crucial role of zinc as a compartmentalized regulator of cellular health and a promising target for therapeutic intervention.