Inside the Cell’s Metal Highway: How Zinc, Manganese, and Iron Reach the ER and Golgi

Deep inside every one of our cells, a bustling manufacturing network works around the clock to fold, modify, and ship out proteins. The endoplasmic reticulum and the Golgi apparatus form the core of this secretory pathway, and their assembly lines depend on something surprisingly small: metal ions. Zinc, manganese, and iron ions act as indispensable cofactors for a wide range of enzymes that carry out protein folding and post-translational modifications such as glycosylation. Without a steady and precisely regulated supply of these metals, the entire production line grinds to a halt. A new review published in Cellular and Molecular Life Sciences by Huihui Li, Yu Zhang, Kexin Yang, and Bing Zhou of Shenzhen University of Advanced Technology and collaborating institutions brings together two decades of research on how these metal ions are transported into and out of the ER and Golgi, and why failures in this traffic control system are increasingly linked to human disease.

The review’s central message is that the ER and Golgi are not merely passive way stations for proteins on their way to the cell surface. They are active hubs of metal ion homeostasis, carefully balancing the influx and efflux of Zn2+, Mn2+, and Fe2+ to meet the demands of the metalloenzymes resident in their lumens. Many of these enzymes simply cannot function without their metal partners. Glycosyltransferases in the Golgi, for example, often require manganese to catalyze the attachment of sugar chains onto proteins, a modification essential for proper protein function, trafficking, and recognition. Zinc, meanwhile, stabilizes protein structures and supports enzymes involved in folding and processing. Iron contributes to enzymes of the secretory pathway as well, although its handling in these organelles remains less well characterized than that of the other two metals. The precise mechanisms governing how each of these ions crosses the membranes of the ER and Golgi have only partially been resolved, and mapping them is one of the field’s central goals.

Over the past twenty years, several transporter families have emerged as key regulators of metal ion homeostasis in the secretory pathway. Among the most prominent are the Zrt/Irt-like proteins, known as ZIPs, which generally import zinc into the cytosol or organelles, and the zinc transporters of the ZnT family, which move zinc in the opposite direction. In the context of the ER and Golgi, specific members of these families have been pinpointed as critical suppliers of zinc to the lumen. The review highlights ZIP13 and ZIP11 in particular, both encoded within the SLC39A gene family, as secretory pathway zinc importers whose dysfunction has tangible consequences for the cell. On the export side, ZnT proteins of the SLC30A family help shape the zinc landscape of these compartments, ensuring that luminal concentrations remain within the narrow window that resident enzymes require.

Manganese transport tells a parallel but distinct story. The secretory pathway Ca2+/Mn2+ ATPase 1, or SPCA1, is a P-type ATPase embedded in Golgi membranes that pumps both calcium and manganese ions into the Golgi lumen at the expense of ATP. This pumping activity maintains the high luminal manganese concentrations needed by Golgi glycosyltransferases, which would otherwise be starved of their essential cofactor. Alongside SPCA1, the review discusses transmembrane protein 165, or TMEM165, another Golgi-resident protein implicated in manganese supply. Mutations in the genes encoding either protein are now recognized causes of congenital disorders of glycosylation, a class of rare inherited diseases in which defective sugar processing leads to multi-system developmental and physiological problems. The convergence of SPCA1 and TMEM165 on the same biochemical pathway underscores how vulnerable glycosylation is to disruptions in metal delivery.

What makes this review particularly timely is its synthesis of the disease connections that have accumulated over recent years. Dysregulation of ER and Golgi metal transporters is increasingly linked not only to congenital disorders of glycosylation but also to connective tissue disorders, neurodegenerative diseases, and cancer. ZIP13, for instance, has been implicated in a spondylocheirodysplastic form of Ehlers-Danlos syndrome, a connective tissue disorder in which defective zinc handling in the secretory pathway compromises the biosynthesis of extracellular matrix components. In the nervous system, altered metal homeostasis in the secretory pathway has been associated with neurodegenerative processes, reflecting the heavy metal demands of neurons and their extensive protein secretory machinery. In cancer, transporter expression patterns shift in ways that can support the altered metabolism and uncontrolled growth of tumor cells, making some of these transporters potential biomarkers or therapeutic targets.

One of the emerging concepts the authors emphasize is metal crosstalk within the secretory pathway. The ER and Golgi do not handle zinc, manganese, and iron in isolation from one another. Competition and cooperation among these ions, and among the transporters that move them, can reshape the metal composition of the entire pathway. When one metal is scarce or its transporter is compromised, the cell may compensate by redistributing others, sometimes with unintended consequences for metalloenzyme function. This interconnectedness means that studying a single transporter in isolation provides only a partial picture. The review argues that a systems-level understanding, one that considers how ZIPs, ZnTs, SPCA1, TMEM165, and iron-handling mechanisms interact, is needed to predict how cells respond to metal stress and how these responses fail in disease.

The technical challenges of studying metal transport in these organelles are considerable. Metal ions cannot be easily visualized in living cells without specialized fluorescent probes, and their concentrations in the ER and Golgi lumen are difficult to measure directly. Much of what is known has come from genetic studies in model organisms, cell biological experiments tracking transporter localization, and biochemical characterization of purified proteins. Each approach has limitations, and the review makes clear that significant gaps remain. For iron in particular, the transporters responsible for moving Fe2+ across ER and Golgi membranes are still not fully identified, and the review frames this as a key open question for the field to address in the coming years.

The authors also point toward future directions that could accelerate progress. Better probes for imaging labile metal ions in specific organelles would allow researchers to watch metal traffic in real time. Structural biology, including cryo-electron microscopy, is beginning to reveal the molecular architectures of transporters like SPCA1 and TMEM165, offering clues about how they discriminate between calcium and manganese or how disease mutations disable them. Genome editing technologies make it possible to model patient-specific transporter mutations in cell lines, creating platforms for testing corrective strategies. And because several of these transporters are membrane proteins accessible from the cytosolic side, they represent plausible drug targets, raising the prospect of pharmacological interventions that could restore metal balance in disorders of glycosylation or mitigate metal-related contributions to neurodegeneration and cancer.

For a field that began with the simple observation that Golgi enzymes need manganese, the scope of what has been learned is striking. The ER and Golgi now appear as sophisticated metal management centers, with dedicated importers, pumps, and regulatory mechanisms tuned to the needs of dozens of metalloenzymes. The review by Li, Zhang, Yang, and Zhou consolidates this knowledge into a coherent framework and, just as importantly, lays out the questions that remain. As the authors note, the precise mechanisms governing metal transport into and out of these organelles are still being elucidated, and the pathophysiological consequences of their disruption extend across an impressive range of human disease. What happens in these microscopic compartments, it turns out, resonates through the entire body, from the skeleton and connective tissue to the brain, and understanding the cell’s metal highway may ultimately open new avenues for treating disorders that have long resisted conventional approaches.

Subject of Research: Metal ion transport mechanisms and homeostasis in the endoplasmic reticulum and Golgi apparatus

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

Article References: Metal ion transport in the ER/Golgi: zinc, manganese, and iron. (n.d.). https://doi.org/10.1007/s00018-026-06487-5

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06487-5

Keywords: endoplasmic reticulum, Golgi apparatus, zinc transport, manganese, iron, ZIP transporters, ZnT transporters, SPCA1, TMEM165, glycosylation, metal ion homeostasis, metalloenzymes