Metallothionein redox biology in the cytoprotective and cytotoxic functions of zinc

A critical aspect of cellular zinc metabolism is the tight control of the picomolar concentrations of free zinc ions and their fluctuations to balance folding and misfolding of proteins, supply of thousands of zinc-requiring proteins with zinc, and dual functions of zinc as either a pro-oxidant or a pro-antioxidant. Zinc/sulfur (cysteine) bonds in proteins have a key role in this control because they generate redox-active coordination environments. Metallothionein (MT) is such a redox-active zinc protein, which couples biochemically to the cellular redox state. The coordination dynamics and redox state of its zinc/thiolate clusters determine cellular zinc availability. A fraction of MT in tissues and cells contains free thiols and disulfides. Thus, MT with seven zinc ions and twenty reduced thiols as characterized by high-resolution 3D structures does not represent its biologically active form. Redox stress affects the zinc and redox buffering capacity of MT and elicits fluctuations of zinc ions that are potent effectors of multiple metabolic and signaling pathways. We are beginning to appreciate the sensitivity of cellular zinc homeostasis to perturbations, the clinical importance of linked zinc and redox imbalances for aging and the development of chronic diseases, and the tangible benefits of preventive and therapeutic nutritional interventions.