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

Abstract

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.

Zinc Nutrition and Inflammation in the Aging Retina

“…Zinc is bound exclusively to the sulfur donors of cysteines in zinc‐thiolate clusters . One MT molecule can bind seven zinc ions, through different binding affinities to metals . With lower zinc binding affinity, MTs react as redox proteins.…”

“…[125] One MT molecule can bind seven zinc ions, through different binding affinities to metals. [117,[125][126][127] With lower zinc binding affinity, MTs react as redox proteins. They sequester or release zinc, depending on the local redox state, thereby trapping, not only any zinc for storage, but also serve as zinc acceptors and donors for other proteins in a dynamic way (zinc buffering in non-steady state conditions).…”

Residue Modification and Mass Spectrometry for the Investigation of Structural and Metalation Properties of Metallothionein and Cysteine-Rich Proteins

“…MT-3, the brain-specific isoform, has been shown to bind neurotoxic metals such as lead [53] and interact with proteins associated with neurodegenerative diseases [54,55,56]. In addition to homeostatic maintenance, it has been suggested that MTs having 20 free-SH thiols, contribute to redox signaling, and balance within the cellular environment [57,58,59]. RM-MS leverages the abundance of reactive thiols on MT to probe its solution structure without the need for high concentrations or crystallization.…”

Selective cysteine modification of metal‐free human metallothionein 1a and its isolated domain fragments: Solution structural properties revealed via ESI‐MS

“…These special properties include binding of up to 7 Zn 21 and Cd 21 , forming two metal-thiolate clustered domains (the a and b-domains) that are joined by a short linker sequence. 2,3 While the biological function(s) of this family of proteins are still debated, it is generally agreed that their functions are connected with zinc and copper homeostasis, [4][5][6][7] redox signalling, [8][9][10] and toxic metal sequestration. [11][12][13][14][15] Despite these many proposed functions, and their capacity to bind so many metals, 16,17 MTs are surprisingly small, flexible proteins that lack optically active structural features.…”