The Role of Metallothionein and Astrocyte-Neuron Interactions in Injury to the CNS

Fung, SJ; Chung, Roger S.; West, AK

doi:10.1142/9789812778949_0006

Cited by 2 publications

(3 citation statements)

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“…372,379−383 With specific reference to the healthy, diseased, or injured brain, MT3 is mainly in neurons, while MT1/2 are mainly in astrocytes. 384 Various forms of stress, inflammation, hypoxia, bacterial and viral infections, and aspects of cell fate (cell cycle/proliferation, differentiation/development, cell death/apoptosis) and cell adhesion/migration are such general processes linked to pathways of MT induction. Translating phenomenology into teleology, that is, what the protein does specifically, will reveal the implications for metal metabolism.…”

Section: Multiplicity Of Mt Genes and Their Regulationmentioning

confidence: 99%

“…In our opinion, statements that try to relate the protein to general observations of redox changes are superficial without identifying targets and should address changes in metal metabolism and resolving the ambiguity of whether the induced protein restricts metal ions or makes them available as would be the case in an antioxidant function when the protein thiols are oxidized. We will discuss general pathways that underlie many diseases and not discuss in detail noncommunicable diseases such as cancer, diabetes, and neurodegeneration, for which a lot of work regarding a positive or negative effect of MTs and a role of MT3 in the brain has been published as apparent from the cited reviews. ,− With specific reference to the healthy, diseased, or injured brain, MT3 is mainly in neurons, while MT1/2 are mainly in astrocytes . Various forms of stress, inflammation, hypoxia, bacterial and viral infections, and aspects of cell fate (cell cycle/proliferation, differentiation/development, cell death/apoptosis) and cell adhesion/migration are such general processes linked to pathways of MT induction.…”

Section: Regulation Of Metallothionein In Biological Space and Timementioning

confidence: 99%

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The Bioinorganic Chemistry of Mammalian Metallothioneins

2021

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The functions, purposes, and roles of metallothioneins have been the subject of speculations since the discovery of the protein over 60 years ago. This article guides through the history of investigations and resolves multiple contentions by providing new interpretations of the structure-stability-function relationship. It challenges the dogma that the biologically relevant structure of the mammalian proteins is only the one determined by X-ray diffraction and NMR spectroscopy. The terms metallothionein and thionein are ambiguous and insufficient to understand biological function. The proteins need to be seen in their biological context, which limits and defines the chemistry possible. They exist in multiple forms with different degrees of metalation and types of metal ions. The homoleptic thiolate coordination of mammalian metallothioneins is important for their molecular mechanism. It endows the proteins with redox activity and a specific pH dependence of their metal affinities. The proteins, therefore, also exist in different redox states of the sulfur donor ligands. Their coordination dynamics allows a vast conformational landscape for interactions with other proteins and ligands. Many fundamental signal transduction pathways regulate the expression of the dozen of human metallothionein genes. Recent advances in understanding the control of cellular zinc and copper homeostasis are the foundation for suggesting that mammalian metallothioneins provide a highly dynamic, regulated, and uniquely biological metal buffer to control the availability, fluctuations, and signaling transients of the most competitive Zn(II) and Cu(I) ions in cellular space and time.

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Section: Multiplicity Of Mt Genes and Their Regulationmentioning

confidence: 99%

Section: Regulation Of Metallothionein In Biological Space and Timementioning

confidence: 99%

The Bioinorganic Chemistry of Mammalian Metallothioneins

2021

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“…MT-3 expression has generally been confined to neurons and some subtypes of astrocytes (Fung et al, 2008), except in specific disease states where oligodendrocytes can develop inclusions positive for MT-3 (Pountney et al, 2011). MT-3 mRNA is decreasing in contrast to MT-1 mRNA and MT-2 mRNA increasing.…”

Section: Mtf-1 and Mts Increase In Oligodendrocytes As They Become Mo...mentioning

confidence: 99%

Developmental regulation of zinc homeostasis in differentiating oligodendrocytes

Elitt

Ross

Wang

et al. 2023

Preprint

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Oligodendrocytes develop through well characterized stages and understanding pathways regulating their differentiation remains an active area of investigation. Zinc is required for the function of many enzymes, proteins and transcription factors, including those important in myelination and mitosis. Our previous studies using the ratiometric zinc sensor chromis-1 demonstrated a reduction in intracellular free zinc concentrations in mature oligodendrocytes compared with earlier stages (Bourassa et al., 2018). We performed a more detailed developmental study to better understand the temporal course of zinc homeostasis across the oligodendrocyte lineage. Using chromis-1, we found a transient increase in free zinc after developing oligodendrocytes were switched into differentiation medium. To gather other evidence for dynamic regulation of free zinc during oligodendrocyte development, qPCR was used to evaluate mRNA expression of the major zinc storage proteins metallothioneins (MTs), and metal regulatory transcription factor 1 (MTF-1) which controls expression of MTs. MT-1, MT-2 and MTF1 mRNAs were all increased several fold in mature oligodendrocytes compared to developing oligodendrocytes. To assess the depth of the zinc buffer, we assayed zinc release from intracellular stores using the oxidizing thiol reagent 2,2'-dithiodipyridine (DTDP). Exposure to DTDP resulted in a ~100% increase in free zinc in developing oligodendrocytes but, paradoxically more modest ~60% increase in mature oligodendrocytes despite the increased expression of MTs. These results suggest that zinc homeostasis is regulated during oligodendrocyte development, that oligodendrocytes are a useful model for studying zinc homeostasis in the central nervous system, and that regulation of zinc homeostasis may be important in oligodendrocyte differentiation.

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The Role of Metallothionein and Astrocyte-Neuron Interactions in Injury to the CNS

Cited by 2 publications

References 0 publications

The Bioinorganic Chemistry of Mammalian Metallothioneins

The Bioinorganic Chemistry of Mammalian Metallothioneins

Developmental regulation of zinc homeostasis in differentiating oligodendrocytes

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