Cadmium effects on superoxide dismutase 1 in human cells revealed by NMR

Panagis Polykretis,Francesca Cencetti,Chiara Donati,Enrico Luchinat,Lucia Banci

doi:10.1016/j.redox.2019.101102

Panagis Polykretis, Francesca Cencetti + Show 3 more

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https://doi.org/10.1016/j.redox.2019.101102

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Journal: Redox Biology	Publication Date: Jan 8, 2019
Citations: 38	License type: cc-by

Affiliation: University of Florence

Abstract

Cadmium is a toxic pollutant that in recent decades has become more widespread in the environment due to anthropogenic activities, significantly increasing the risk of exposure. Concurrently, a continually growing body of research has begun to enumerate the harmful effects that this heavy metal has on human health. Consequently, additional research is required to better understand the mechanism and effects of cadmium at the molecular level. The main mechanism of cadmium toxicity is based on the indirect induction of severe oxidative stress, through several processes that unbalance the anti-oxidant cellular defence system, including the displacement of metals such as zinc from its native binding sites. Such mechanism was thought to alter the in vivo enzymatic activity of SOD1, one of the main antioxidant proteins of many tissues, including the central nervous system. SOD1 misfolding and aggregation is correlated with cytotoxicity in neurodegenerative diseases such as amyotrophic lateral sclerosis. We assessed the effect of cadmium on SOD1 folding and maturation pathway directly in human cells through in-cell NMR. Cadmium does not directly bind intracellular SOD1, instead causes the formation of its intramolecular disulfide bond in the zinc-bound form. Metallothionein overexpression is strongly induced by cadmium, reaching NMR-detectable levels. The intracellular availability of zinc modulates both SOD1 oxidation and metallothionein overexpression, strengthening the notion that zinc-loaded metallothioneins help maintaining the redox balance under cadmium-induced acute stress.

Highlights

Cadmium is a potent environmental and food contaminant that is ranked as the seventh most hazardous substance for human health when considering both toxicity and exposure frequency [1]
Under basal conditions, a fraction of overexpressed superoxide dismutase 1 (SOD1) binds the Zn2+ available in the growth medium while the remaining fraction is in the apo state, whereas addition of Zn2+ allows the complete Zn2+ binding to SOD1 with one Zn2+ per monomer (E,Zn-SOD1), as previously reported [34] (Fig. 1a)
The histidine signals of intracellular SOD1 in the Cd2+-treated cells did not change with respect to the untreated cells, matched those of apo-SOD1 metallated with Zn2+ in vitro and differed from those of apo-SOD1 metallated in vitro with increasing equivalents of Cd2+ per SOD1 monomer (Fig. 1b)

Summary

Introduction

Cadmium is a potent environmental and food contaminant that is ranked as the seventh most hazardous substance for human health when considering both toxicity and exposure frequency [1]. It has been classified as a category 1 carcinogen by the International Agency for Research on Cancer [2]. Cadmium compounds are very soluble in water, facilitating its uptake by plants and human exposure as a food and tobacco contaminant [4,5]. The main accumulation sites of cadmium are kidneys, liver, lungs, bone, testes and brain, where it causes severe oxidative stress and other detrimental effects [7,8]

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