Metallothioneins (MTs) in the human eye: a perspective article on the zinc-MT redox cycle

Metallothioneins (MTs) are zinc-ion-binding proteins with a wide range of functions, among which are neuroprotection, maintenance of cellular zinc homeostasis, and defense against oxidative damage and inflammation. The human eye is enriched in MTs, and multiple isoforms may contribute to distinct antioxidant defense mechanisms in various ocular tissues. Zinc is a main regulator of MT gene and protein expression, and we recently applied bioanalytical techniques to address key questions on its relationship with MTs, including the stoichiometry of zinc-MT, the fate of zinc tracers ((nat)Zn and (68)Zn) in MTs during activation by exogenous zinc and cytokines, and the concentration of MTs in human ocular cells. We found that exogenously introduced zinc induced a potent de novo synthesis of MTs as well as a strong inhibition of pro-inflammatory cytokines. Zinc and cytokines also promote a stoichiometric transition of the MT complex from Zn6Cu1-MT to Zn7-MT, suggesting that MTs may interact more effectively with reactive oxygen species to decrease potential oxidative damage. Levels of MTs decrease with aging and disease, which may result in zinc release that is potentially cytotoxic. This state is also observed with increased oxidative stress and inflammation, suggesting that the antioxidant function of MTs has been impaired. In this review we propose a working model of the "zinc-metallothionein redox cycle" to regenerate and enhance the antioxidant function of MTs with the aim of combating the progression of these disease states.