Metallothionein protects against oxidative stress-induced lysosomal destabilization

Baird, Sarah K.; Kurz, Tino; Brunk, Ulf T.

doi:10.1042/bj20051143

Cited by 134 publications

(151 citation statements)

References 52 publications

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“…MTs are a class of low-abundance cytoplasmic SH-rich proteins binding a variety of metals, iron included, 30 whose upregulation is highly protective against a number of harmful conditions, in particular those in which oxidative stress is involved. 29,[53][54][55][56][57] These proteins are often overexpressed in various cancers, making them more resistant to irradiation and drugs that induce oxidative stress. 58 In the present work, MT1A and MT2A were found poorly expressed in HTC cells under basal conditions, but were easily upregulated by ZnCl 2 .…”

Section: Discussionmentioning

confidence: 99%

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Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

et al. 2015

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, tandem fluorescent microtubule-associated protein 1 light chain 3 A/B (green/red fluorescent proteins chimera); TNFRSF1A/TNFR1, tumor necrosis factor receptor superfamily member 1A; TNFRSF1B/TNFR2, tumor necrosis factor receptor superfamily member 1B.Lysosomal membrane permeabilization (LMP) induced by oxidative stress has recently emerged as a prominent mechanism behind TNF cytotoxicity. This pathway relies on diffusion of hydrogen peroxide into lysosomes containing redox-active iron, accumulated by breakdown of iron-containing proteins and subcellular organelles. Upon oxidative lysosomal damage, LMP allows relocation to the cytoplasm of low mass iron and acidic hydrolases that contribute to DNA and mitochondrial damage, resulting in death by apoptosis or necrosis. Here we investigate the role of lysosomes and free iron in death of HTC cells, a rat hepatoma line, exposed to TNF following metallothionein (MT) upregulation. Iron-binding MT does not normally occur in HTC cells in significant amounts. Intracellular iron chelation attenuates TNF and cycloheximide (CHX)-induced LMP and cell death, demonstrating the critical role of this transition metal in mediating cytokine lethality. MT upregulation, combined with starvation-activated MT autophagy almost completely suppresses TNF and CHX toxicity, while impairment of both autophagy and MT upregulation by silencing of Atg7, and Mt1a and/or Mt2a, respectively, abrogates protection. Interestingly, MT upregulation by itself has little effect, while stimulated autophagy alone depresses cytokine toxicity to some degree. These results provide evidence that intralysosomal iron-catalyzed redox reactions play a key role in TNF and CHX-induced LMP and toxicity. The finding that chelation of intralysosomal iron achieved by autophagic delivery of MT, and to some degree probably of other ironbinding proteins as well, into the lysosomal compartment is highly protective provides a putative mechanism to explain autophagy-related suppression of death by TNF and CHX.

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Section: Discussionmentioning

confidence: 99%

“…Since MT upregulation has been reported to protect against LMP induced by various kinds of oxidative stress, 29 we focused on this group of proteins, which bind a variety of metals, including iron (for a review see ref. 30 ) and, particularly, on the inducible MT1A and MT2A isoforms.…”

Section: Effect Of Mt (Metallothionein) Autophagy On Tnf and Chx Toximentioning

confidence: 99%

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

et al. 2015

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“…The cytosol contains a range of iron-binding proteins, such as metallothioneins, Hsp70 and ferritin (Baird et al, 2006, Kurz and Brunk, 2009, Kurz et al, 2011. These can all be autophagocytosed and then are able to bind lysosomal redox-active iron for a limited period of time until they are degraded.…”

Section: The Role Of Lysosomes In Intracellular Iron Metabolismmentioning

confidence: 99%

The role of lysosomes in iron metabolism and recycling

Kurz

Eaton

Brunk

2011

The International Journal of Biochemistry & Cell Biology

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Iron is the most abundant transition metal in the earths crust. It cycles easily between ferric (oxidized; Fe(III)) and ferrous (reduced; Fe(II)) and readily forms complexes with oxygen, making this metal a central player in respiration and related redox processes. However, loose iron, not within heme or iron-sulfur cluster proteins, can be destructively redox-active, causing damage to almost all cellular components, killing both cells and organisms. This may explain why iron is so carefully handled by aerobic organisms. Iron uptake from the environment is carefully limited and carried out by specialized iron transport mechanisms. One reason that iron uptake is tightly controlled is that most organisms and cells cannot efficiently excrete excess iron. When even small amounts of intracellular free iron occur, most of it is safely stored in a non-redox-active form in ferritins. Within nucleated cells, iron is constantly being recycled from aged iron-rich organelles such as mitochondria and used for construction of new organelles. Much of this recycling occurs within the lysosome, an acidic digestive organelle. Because of this, most lysosomes contain relatively large amounts of redox-active iron and are therefore unusually susceptible to oxidant-mediated destabilization or rupture. In many cell types, iron transit through the lysosomal compartment can be remarkably brisk. However, conditions adversely affecting lysosomal iron handling (or oxidant stress) can contribute to a variety of acute and chronic diseases. These considerations make normal and abnormal lysosomal handling of iron central to the understanding and, perhaps, therapy of a wide range of diseases

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“…Templeton and Cherian (1991) found that the Gradually, the facts that MTs are involved in the homeostatic regulation of metals which provides a reservoir of metals for other metalloproteins or metalloenzymes, in heavy metal detoxification, in protection of tissues against various forms of oxidative injuries and transferring of essential metals (Coyle et al, 2002;Baird et al, 2006) (Figure 1). All the phenomena could be elucidated by chemical property of the thiolate bond (Suzuki et al, 2002).…”

Section: Structure Characteristics Of Mtsmentioning

confidence: 99%

Characteristics, functions, and applications of metallothionein in aquatic vertebrates

Weichao

Mao

et al. 2014

Front. Mar. Sci.

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The documents on Metallothioneins (MTs) in aquatic creatures, especially focusing on their function as biomarkers in environmental monitoring programmes, are vast and increasing. There are, however, few papers to summary the physiological role of MTs in aquatic organisms especially on development. The multifaceted roles of MTs include involvement in homeostasis, protection against heavy metals and oxidant damages, and metabolic regulation, sequestration and/or redox control. In this paper, we have collected published information on MTs in aquatic organisms-pisces, amphibians, mammals, etc., and analyzed their function in these aquatic animals. MTs have four main functions in aquatic vertebrate. They are respectively bioaccumulation of toxic metals and detoxification, homeostatic regulation of metals, protection against oxidative stress and neuroprotective mechanism. MTs separate in different tissues and they have various distributions in different tissues of aquatic vertebrate, including liver, gills, kidney, testes, and brain. MTs can be induced by a variety of environmental and physiological factors, among which, heavy metals are the main kind of MTs inducers in aquatic vertebrate. Here we pay more attention on the essential metals copper (Cu) and zinc (Zn) and the non-essential metals cadmium (Cd), silver (Ag), lead (Pb), and mercury (Hg).

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Metallothionein protects against oxidative stress-induced lysosomal destabilization

Cited by 134 publications

References 52 publications

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

The role of lysosomes in iron metabolism and recycling

Characteristics, functions, and applications of metallothionein in aquatic vertebrates

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