Zinc efflux through lysosomal exocytosis prevents zinc-induced toxicity

Kukic, Ira; Kelleher, Shannon L.; Kiselyov, Kirill

doi:10.1242/jcs.145318

Cited by 62 publications

(78 citation statements)

References 66 publications

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“…Further studies then indicated that lysosomes and their networks might represent a special detoxification mechanism for transition metal toxicity [30]. Our current findings concur with this view, but also indicate the likely involvement of melanosomes in these circumstances.…”

Section: Discussionsupporting

confidence: 88%

Increases in Intracellular Zinc Enhance Proliferative Signaling as well as Mitochondrial and Endolysosomal Activity in Human Melanocytes

Rudolf¹,

Rudolf²

2017

Cell Physiol Biochem

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Background/Aims: Zinc (Zn) is an important microelement required by skin cells for a variety of biological processes. The role of Zn in melanocyte proliferation and homeostasis has to date not been investigated. Methods: Human dermal melanocytes were isolated from patients and their proliferative activity determined along with both total and labile Zn content. Subsequently, changes in proliferation as well as in Zn content were determined upon exposure of the dermal melanocytes to external Zn. Further in-depth analyses were undertaken aimed at measuring the expression of proliferation-related proteins (determined by immunoblotting and densitometry), as well as changes in mitochondrial biogenesis and membrane potential (assessed by fluorescence-based cellometry) along with endolysosomal activity (determined by spectrofluorimetrically-measured elevation in fluorescence of lysosomal-aimed non-fuorescent substrate). Results: Human skin melanocytes accumulate externally added Zn, a process which dose-dependently enhances their injury or proliferative activity. Enhanced proliferation is accompanied by an increased expression of the proteins AKT3, ERK1/2, c-MYC and CYCD. In addition, Zn-enriched melanocytes exhibit enhanced mitochondrial biogenesis, with individual mitochondria possessing stabilized mitochondrial membrane potential as well as showing elevated ATP and superoxide levels. Moreover, upon external exposure, Zn enters lysosomes/melanosomes, the activity of which is stimulated along with the process of autophagy. Conclusion: The determination of the unique Zn-dependent stimulation of melanocytes and in particular the enhancement of the cells’ mitochondrial as well as lysosomal/melanosomal activities may prove important in tracing the sequence of steps in the process of melanomagenesis.

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Section: Discussionsupporting

confidence: 88%

Increases in Intracellular Zinc Enhance Proliferative Signaling as well as Mitochondrial and Endolysosomal Activity in Human Melanocytes

Rudolf¹,

Rudolf²

2017

Cell Physiol Biochem

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“…However, several possibilities exist that may explain this finding. First, since the D 103 E variant was associated with lysosomes, Zn efflux could occur via non-classical lysosomal-mediated pathways [30]. As an alternative explanation, although ZnT1 expression was reduced, the rate of ZnT1-mediated Zn efflux may have been increased by intrinsic factors like pH and calcium [31].…”

Section: Genetic Variation In Slc30a2 Is a Major Modifier Of Milk [Zn]mentioning

confidence: 99%

Exome Sequencing of SLC30A2 Identifies Novel Loss- and Gain-of-Function Variants Associated with Breast Cell Dysfunction

Alam

Hennigar

Gallagher

et al. 2015

J Mammary Gland Biol Neoplasia

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The zinc (Zn) transporter ZnT2 (SLC30A2) is expressed in specialized secretory cells including breast, pancreas and prostate, and imports Zn into mitochondria and vesicles. Mutations in SLC30A2 substantially reduce milk Zn concentration ([Zn]) and cause severe Zn deficiency in exclusively breastfed infants. Recent studies show that ZnT2-null mice have low milk [Zn], in addition to profound defects in mammary gland function during lactation. Here, we used breast milk [Zn] to identify novel non-synonymous ZnT2 variants in a population of lactating women. We also asked whether specific variants induce disturbances in intracellular Zn management or cause cellular dysfunction in mammary epithelial cells. Healthy, breastfeeding women were stratified into quartiles by milk [Zn] and exonic sequencing of SLC30A2 was performed. We found that 36% of women tested carried non-synonymous ZnT2 variants, all of whom had milk Zn levels that were distinctly above or below those in women without variants. We identified 12 novel heterozygous variants. Two variants (D(103)E and T(288)S) were identified with high frequency (9 and 16%, respectively) and expression of T(288)S was associated with a known hallmark of breast dysfunction (elevated milk sodium/potassium ratio). Select variants (A(28)D, K(66)N, Q(71)H, D(103)E, A(105)P, Q(137)H, T(288)S and T(312)K) were characterized in vitro. Compared with wild-type ZnT2, these variants were inappropriately localized, and most resulted in either 'loss-of-function' or 'gain-of-function', and altered sub-cellular Zn pools, Zn secretion, and cell cycle check-points. Our study indicates that SLC30A2 variants are common in this population, dysregulate Zn management and can lead to breast cell dysfunction. This suggests that genetic variation in ZnT2 could be an important modifier of infant growth/development and reproductive health/disease. Importantly, milk [Zn] level may serve as a bio-reporter of breast function during lactation.

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“…We also used bafilomycin to raise cytosolic Zn 2+ ( Fig. S3F) by inhibiting lysosomal sequestration of the ion (Kukic et al, 2014). Again, this manoeuvre caused loss of stress fibres and appearance of filopodia (Fig.…”

Section: +mentioning

confidence: 99%

Reciprocal regulation of actin cytoskeleton remodelling and cell migration by Ca2+ and Zn2+: role of TRPM2 channels

Abuarab

Sivaprasadarao

2016

Journal of Cell Science

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Zinc efflux through lysosomal exocytosis prevents zinc-induced toxicity

Abstract: Zn2+ is an essential micronutrient and an important ionic signal whose excess, as well as scarcity, is detrimental to cells.

Cited by 62 publications

References 66 publications

Increases in Intracellular Zinc Enhance Proliferative Signaling as well as Mitochondrial and Endolysosomal Activity in Human Melanocytes

Increases in Intracellular Zinc Enhance Proliferative Signaling as well as Mitochondrial and Endolysosomal Activity in Human Melanocytes

Exome Sequencing of SLC30A2 Identifies Novel Loss- and Gain-of-Function Variants Associated with Breast Cell Dysfunction

Reciprocal regulation of actin cytoskeleton remodelling and cell migration by Ca2+ and Zn2+: role of TRPM2 channels

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