Disruption of iron homeostasis in Saccharomyces cerevisiae by high zinc levels: a genome‐wide study

Abstract

SummaryZinc is an essential metal that, when in excess, can be deleterious to the cell. Therefore, homeostatic mechanisms for this cation must be finely tuned. To better understand the response of yeast in front of an excess of zinc, we screened a systematic deletion mutant library for altered growth in the presence of 6 mM zinc. Eighty-nine mutants exhibited increased zinc sensitivity, including many genes involved in vacuolar assembling and biogenesis. Interestingly, a mutant lacking the Aft1 transcription factor, required for the transcriptional response to iron starvation, was found to be highly sensitive to zinc. Genomewide transcriptional profiling revealed that exposure to 5 mM ZnCl 2 results in rapid increase in the expression of numerous chaperones required for proper protein folding or targeting to vacuole and mitochondria, as well as genes involved in stress response (mainly oxidative), sulphur metabolism and some components of the iron regulon. The effect of the lack of Aft1 both in the absence and in the presence of zinc overload was also investigated. Exposure to high zinc generated reactive oxygen species and markedly decreased glutathione content. Interestingly, zinc excess results in decreased intracellular iron content and aconitase and cytochrome c activities in stationary-phase cultures. These findings suggest that high zinc levels may alter the assembly and/or function of iron-sulphur-containing proteins, as well as the biosynthesis of haem groups, thus establishing a link between zinc, iron and sulphur metabolism.

A Genome-Wide Enhancer Screen Implicates Sphingolipid Composition in Vacuolar ATPase Function in Saccharomyces cerevisiae

“…Deletion of some trafficking-related genes has been shown to result in sensitivity to zinc, calcium, or alkaline conditions (Serrano et al 2004;Sambade et al 2005;Pagani et al 2007). Our strategy for screening effectively detected reduced VATPase activity levels to $10% of wild-type yeast (scored as ,50% of activity in the vma21QQ mutant strain).…”

“…Genome-wide screens for zinc or calcium (at pH 7.5) sensitivity have found genes that do not directly contribute to V-ATPase function yet show sensitivity to excess metals (Sambade et al 2005;Pagani et al 2007). An example is deletion of the vacuolar zinc transporter Zrc1p, which confers zinc sensitivity even though vacuolar acidification is normal (data not shown).…”

OmZnT1 and OmFET, two metal transporters from the metal-tolerant strain Zn of the ericoid mycorrhizal fungus Oidiodendron maius, confer zinc tolerance in yeast

“…Several observations suggest that the uptake and homeostasis of iron and zinc, both essential elements but toxic at high cellular concentrations, are intertwined. Pagani et al (2007) reported the disruption of Fe homeostasis by high Zn. For instance, it was shown that Zn stress could induce the expression of several components of iron uptake (Fet3, Ftr1).…”

“…All organisms have therefore developed homeostatic mechanisms aimed to ensure the minimal zinc levels required for normal metabolism but also to avoid zinc intoxication (Pagani et al, 2007). O. maius Zn is a metal tolerant ericoid mycorrhizal isolate derived from roots of V. myrtillus growing in a heavy metal polluted site where zinc was the most abundant contaminant ( Martino et al, 2000).…”

Vsl1p cooperates with Fsv1p for vacuolar protein transport and homotypic fusion in Schizosaccharomyces pombe

“…In plant cells, it was speculated that a vacuolar membrane transporter AtMTP1 would function in maintaining the subcellular zinc concentration for the ion homeostasis, suggesting that vacuoles are important organelles for tolerance to high zinc exposure (Kobae et al, 2004). In fact, in budding yeast, mutants in vacuolar organization are sensitive to high zinc concentration (Pagani et al, 2007). Based on this idea, although no obvious phenotype on vacuolar morphology was observed, possible perturbation in vacuolar function would induce the zinc sensitivity in single disruptants vsl1D and fsv1D.…”