The redox biology of redox-inert zinc ions

Abstract

Zinc(II) ions are redox-inert in biology. Yet, their interaction with sulfur of cysteine in cellular proteins can confer ligandcentered redox activity on zinc coordination sites, control protein functions, and generate signalling zinc ions as potent effectors of many cellular processes. The specificity and relative high affinity of binding sites for zinc allow regulation in redox biology, free radical biology, and the biology of reactive species. Understanding the role of zinc in these areas of biology requires an understanding of how cellular Zn2+ is homeostatically controlled and can serve as a regulatory ion in addition to Ca2+, albeit at much lower concentrations. A rather complex system of dozens of transporters and metallothioneins buffer the relatively high (hundreds of micromolar) total cellular zinc concentrations in such a way that the available zinc ion concentrations are only picomolar but can fluctuate in signalling. The proteins targeted by Zn2+ transients include enzymes controlling phosphorylation and redox signalling pathways. Networks of regulatory functions of zinc integrate gene expression and metabolic and signalling pathways at several hierarchical levels. They affect enzymatic catalysis, protein structure and protein-protein/biomolecular interactions and add to the already impressive number of catalytic and structural functions of zinc in an estimated three thousand human zinc proteins. The effects of zinc on redox biology have adduced evidence that zinc is an antioxidant. Without further qualifications, this notion is misleading and prevents a true understanding of the roles of zinc in biology. Its antioxidant-like effects are indirect and expressed only in certain conditions because a lack of zinc and too much zinc have pro-oxidant effects. Teasing apart these functions based on quantitative considerations of homeostatic control of cellular zinc is critical because opposite consequences are observed depending on the concentrations of zinc: pro-or anti-apoptotic, pro-or anti-inflammatory and cytoprotective or cytotoxic. The article provides a biochemical basis for the links between redox and zinc biology and discusses why zinc has pleiotropic functions. Perturbation of zinc metabolism is a consequence of conditions of redox stress. Zinc deficiency, either nutritional or conditioned, and cellular zinc overload cause oxidative stress. Thus, there is causation in the relationship between zinc metabolism and the many diseases associated with oxidative stress. Highlights• Redox-inert zinc ions regulate some aspects of redox biology and the biology or reactive species.• Control of cellular zinc homeostasis determines antioxidant-like or pro-oxidant effects.• Zinc deficiency and overload cause oxidative stress.• Disorders of zinc metabolism are a cause or consequence of diseases associated with oxidative stress.Abbreviations ER, endoplasmic reticulum; GCL, glutamate cysteine ligase; MT, metallothionein; MTF-1, metal regulatory element (MRE)-binding transcription factor-1; NOS, nitric oxide syntha...

Resveratrol attenuates hypoxia-induced neuronal cell death, inflammation and mitochondrial oxidative stress by modulation of TRPM2 channel

“…Zn 2+ as a component of some antioxidant enzymes contributes to reducing excessive ROS generation in several cells and neurons 38 . Free Zn 2+ has apoptosis and oxidant actions via accumulation in the mitochondria for neurons 27 . Hence, intracellular free Zn 2+ depletion causes decrease in mitochondria ROS generation, caspase activities and [Ca 2+ ] i concentrations via increase of rGSH and GPx antioxidant levels in the renal collecting duct cells 45 .…”

“…Accumulating evidence indicated that an increase of intracellular free Zn 2+ concentration induces excessive ROS generation 27,28 . After the finding observable increase in the intracellular ROS generation in the SH-SY5Y cells, we suspected increase of the intracellular free Zn 2+ concentration.…”

“…However, its fluorescence intensity was decreased in the RSV + HYPX and 2-APB + HYPX groups by the RSV and 2-APB treatments (p ≤ 0.001). TPEN is an inhibitor of the intracellular free Zn 2+ concentration 27 . After TPEN treatment (100 nM) as a selective Zn 2+ chelator, almost fully protected HYPX-induced oxidative neurotoxicity, indicating a vital role of a rising intracellular free Zn 2+ concentration in HYPX-induced neurotoxicity (Fig.…”

Zink und Lebererkrankungen

“…Für mehr als 300 Enzyme ist das Spurenelement eine essenzielle Komponente für deren katalytische Wirkungen. Zink übt strukturelle Wirkungen auf verschiedene Transkriptionsfaktoren aus und reguliert Hormone, Hormonrezeptoren und die Genexpression [3][4] [5]. Es ist essenziell für die angeborene und erworbene Immunität sowie enzymatischer Cofaktor in der Regulation des Kohlenhydrat-, Fett-und Eiweißstoffwechsels [3][5] [6].…”

Zinc Differentially Modulates the Assembly of Soluble and Polymerized Vimentin

“…On the other hand, zinc can induce cellular effects by modulating the activity of transcription factors [33] and phosphatases [34]. Moreover, zinc can influence protein and cellular redox status due to its potential pro-antioxidant or pro-oxidant roles [35,36]. Therefore, the interactions between zinc and vimentin in vitro and in cells can be complex, and their delineation requires careful assessment.…”