Zinc: From Biological Functions to Therapeutic Potential

Abstract

The trace element zinc (Zn) displays a wide range of biological functions. Zn ions control intercellular communication and intracellular events that maintain normal physiological processes. These effects are achieved through the modulation of several Zn-dependent proteins, including transcription factors and enzymes of key cell signaling pathways, namely those involved in proliferation, apoptosis, and antioxidant defenses. Efficient homeostatic systems carefully regulate intracellular Zn concentrations. However, perturbed Zn homeostasis has been implicated in the pathogenesis of several chronic human diseases, such as cancer, diabetes, depression, Wilson's disease, Alzheimer's disease, and other age-related diseases. This review focuses on Zn's roles in cell proliferation, survival/death, and DNA repair mechanisms, outlines some biological Zn targets, and addresses the therapeutic potential of Zn supplementation in some human diseases.

Keywords: DNA repair; cell death; cell proliferation; therapeutic target; zinc signaling; zinc signals; zinc transporters.

Figure 1

Schematic illustration of zinc (Zn) homeostasis mechanisms and potential subcellular locations of Zn channels. Regulation of cellular zinc fluxes in and out of the cell and cellular compartments is controlled by several Zrt- and Irt-like proteins (ZIP; blue)—the importers—and Zn transporters (ZnT; orange)—the exporters. Metallothioneins (MT; grey) are also key proteins in Zn homeostasis; MT act as Zn buffers by binding to these ions and releasing them into the cytoplasm to increase free intracellular Zn pools, according to cellular needs. Arrows indicate the direction of Zn mobilization through Zn channels. (Figure created with Servier Medical Art and Biorender).

Figure 2

Integration of extracellular and intracellular Zn signals and the labile Zn pool. Zn can increase the affinity of several ligands (e.g., neurotransmitters, growth factors, cytokines, hormones, among others) to their corresponding receptors, thus promoting the initiation of intracellular signaling pathways. These extracellular stimuli can also directly or indirectly affect intracellular Zn status by modulating the transcriptional regulation of Zn-related genes. Such interactions generate several Zn-related responses, such as modulation of Zn transporters and release of Zn from intracellular compartments and MT, all of which increase the intracellular Zn pool. The intracellular labile Zn serves various functions by modulating Zn-dependent proteins from different signaling cascades related to cellular events such as proliferation, growth, survival, and apoptosis, among others. Extracellular Zn can also directly bind to Zn receptors such as ZnR/GPR39 and initiate intracellular signaling cascades. (Figure created with Biorender).

Figure 3

Targets of Zn in cell proliferation. Zn increases the affinity of insulin growth factor (IGF) and epidermal growth factor (EGF) for its receptors. Activation of IGF and EGF initiates several signaling cascades, such as MAPK/ERK, PI3K/AKT, and PKC, to stimulate cell growth and proliferation. The role of Zn in the modulation of NF-kB is still controversial since both activator and inhibitory roles have been described. Lastly, Zn also plays a role in the promotion of thymidine kinase (TK) mRNA synthesis, a key enzyme for cell cycle progression. The red question mark (?) represents the nonconsensual effects of Zn on NF-kB signaling. (Figure created with Biorender).

Figure 4

The effects of Zn on the regulation of cell death and survival mechanisms. Most studies show that under physiological conditions, Zn exhibits antiapoptotic functions. However, reports of proapoptotic effects of Zn have also been described. The effects of Zn on cell death and survival pathways seem to depend on cell type, context, and concentration. The enzymatic function of proapoptotic proteins such as caspases, Ca²⁺/Mg²⁺-dependent endonuclease, and BAX are normally inactivated by Zn. However, antiapoptotic proteins, such as NF-kB-induced survival molecules, BAD, and growth, proliferation, and survival regulators, such as ERK and AKT, are usually activated by Zn. Taken together, these effects usually result in the prevention of apoptosis. However, given that other conditions may influence Zn effects, it is possible that Zn may also regulate these targets to promote proapoptotic effects. The role of Zn in modulating P53 activity is still controversial, as both activator and inhibitory roles have been described. (Figure created with Biorender)

Figure 5

Biological roles of Zn. Zn is a vital trace element and displays various fundamental biological functions. Zn mediates extracellular communication by interacting with several receptors in different cell types. It also acts intracellularly, modulating key signaling pathways. The regulation of cell proliferation and apoptosis also requires Zn. The DNA damage response (DDR) mechanisms are also Zn-dependent since several damage-sensing and repair proteins use Zn for structural, catalytic, and regulatory functions. The role of Zn as an antioxidant element and regulator of cell antioxidant defenses is also known. (Figure created with Biorender)