Cellular zinc homeostasis

Zn shows a variety of effects within the nervous system, thereby requiring that levels of zinc are regulated to a very precise level. A fine balance between ion sequestration, intracellular buffering, and extrusion exists in order to maintain cellular zinc homeostasis. A family of proteins known as metallothioneins regulates zinc sequestration and buffering, while zinc uptake and extrusion is mediated by membrane-associated zinc transporters. Mitochondria may serve as the pool of histochemically reactive zinc in neurons and glial cells. 

Figure 2 Cellular zinc homeostasis. Zinc is delivered to the cytoplasm from either the extracellular space or vesicles within the cell by members of the ZIP family of transporters. A rise in cellular zinc results in activation and nuclear translocation of MTF-1. In the nucleus, MTF-1 regulates the transcription of a set of target genes, including MT and ZnT-1. MT will bind zinc, and ZnT-1 will transport zinc out across the plasma membrane. MT may govern the delivery of zinc to other proteins within the cell. Other members of the CDF family transport zinc into vesicles.

In mammals, as in yeast, several different metallothionein isoforms are known, each with a particular tissue distribution (Vasak and Hasler, 2000). Their synthesis is regulated at the level of transcription not only by copper (as well as the other divalent metal ions cadmium, mercury and zinc) but also by hormones, notably steroid hormones, that affect cellular differentiation. Intracellular copper accumulates in metallothionein in copper overload diseases, such as Wilson s disease, forming two distinct molecular forms one with 12 Cu(I) equivalents bound, in which all 20 thiolate ligands of the protein participate in metal binding the other with eight Cu(I)/ metallothionein a molecules, with between 12-14 cysteines involved in Cu(I) coordination (Pountney et ah, 1994). Although the role of specific metallothionein isoforms in zinc homeostasis and apoptosis is established, its primary function in copper metabolism remains enigmatic (Vasak and Hasler, 2000). 

While unicellular fungi do not require metal transport systems, multi-cellular fungi and plants most certainly do, and we consider their transport in plants, and then consider how metal ions are sequestered in storage compartments before addressing their homeostasis. Once again, we consider in turn these processes for iron, copper and zinc. Since iron metabolism has been most intensively studied in S. cerevisiae, of all the fungi, we will focus our attention on iron homeostatic mechanisms, however, as the reader will see shortly, copper and zinc homeostasis have many similarities. 

Concomitant expression of metallothioneins (MTs) and metalloproteinases (MMPs) occurs in skeletal muscle that has experienced an injury (Lecker et al. 2004 Warren et al. 2007). MTs are small (12-14 kDa), ubiquitous, cysteine-rich, zinc-binding proteins which are primarily produced in the liver and released into the circulation (Tapiero and Tew 2003). Upon release into the circulation these proteins play a pivotal role in cellular processes to render protection to all tissues of the body. In skeletal muscle, MTs initiate anti-inflammatory and anti-apoptotic signaling cascades, reduce reactive oxygen species (ROS)-induced cytotoxicity, protect against ROS-induced DNA degradation, and maintain zinc homeostasis... 

A number of bacterial metal transporters belong to the family of ATP-binding cassette (ABC) transporter system (see Metallochaperones Metal Ion Homeostasis) These systems constitute one of the most abundant superfamilies of proteins. They are involved in the transport of a wide variety of substances and in many cellular processes. The zinc transporter ZnuA from E. Coli and Synechocystis sp. 6803, the proposed zinc transporter TroA from Treponema pallidum, and the proposed manganese transporter Streptococcus pneumoniae surface antigen, PsaA, are placed in cluster 9 of the ABC transporters. ... 

While the primary physiological role of MT involves the homeostasis of zinc and copper, it remains that MT also has a role in the cellular defense against cadmium and mercury. In addition, being a thiol containing protein MT has the potential to be an effective free radical scavenger, therefore, important in regulating the cellular redox-state. 

While direct interactions of cadmium ions with DNA appear to be of little importance, interactions with proteins are of high significance. Especially the DNA repair inhibitions but also altered cell proliferation and/or diminished cell cycle control have frequently been observed at low, non-cytotoxic concentrations of cadmium, raising the question of particularly sensitive targets of cadmium ions. Relevant mechanisms include elevated levels of ROS, interactions with homeostasis and cellular functions of essential metal ions like zinc, calcium, and iron and the interference with cellular redox regulation. 

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