Metal ion transport in the ER/Golgi: zinc, manganese, and iron

The endoplasmic reticulum (ER) and Golgi apparatus form the central hub of the secretory pathway, where many metal-dependent enzymes carry out essential functions including protein folding and post-translational modifications such as glycosylation. Metal ions such as zinc, manganese, and iron ions serve as indispensable cofactors for these enzymes; however, the precise mechanisms governing their transport into and out of these organelles remain to be fully elucidated. Over the past two decades, several transporter families-including Zrt/Irt-like proteins (ZIPs), zinc transporters (ZnTs), secretory pathway Ca 2+ /Mn 2+ ATPase 1 (SPCA1), and transmembrane protein 165 (TMEM165)-have been identified as key regulators of metal ion homeostasis in the ER/Golgi apparatus. The dysregulation of these transporters is increasingly linked to human diseases, ranging from congenital disorders of glycosylation and connective tissue disorders to neurodegenerative diseases and cancer. This review provides a comprehensive overview of current knowledge regarding the transport mechanisms of Zn 2+ , Mn 2+ , and Fe 2+ within the ER/Golgi apparatus. We discuss the central role of the ER/Golgi in metal ion homeostasis, the metal ion transporters involved, and the pathophysiological consequences of disrupted metal ion transport. We also highlight emerging concepts, such as metal crosstalk within the secretory pathway, and propose future directions for this rapidly evolving field.