Abstract
Despite constant efforts to maintain a clean environment, heavy metal pollution continues to raise challenges to the industrialized world. Exposure to heavy metals is detrimental to living organisms, and it is of utmost importance that cells find rapid and efficient ways to respond to and eventually adapt to surplus metals for survival under severe stress. This chapter focuses on the attempts done so far to elucidate the calcium-mediated response to heavy metal stress using the model organism Saccharomyces cerevisiae. The possibilities to record the transient elevations of calcium within yeast cells concomitantly with the heavy metal exposure are presented, and the limitations imposed by interference between calcium and heavy metals are discussed.
Keywords
- heavy metal
- calcium
- stress adaptation
- Saccharomyces cerevisiae
- aequorin
1. Introduction
Responding to environmental stimuli is a prerequisite for cell adaptation to the ever-changing conditions in the cell surroundings. Stress conditions such as sudden changes of temperature, pH, irradiation, or elevations in various chemicals concentration need to be sensed by the cell in order to respond and adapt to these changes. Calcium ions are one of the most widespread second messengers in the eukaryotic cell, being responsible for triggering many responses to external stress conditions [1]. Various biotic and abiotic stresses induce an increase in cytosolic calcium ions ([Ca2+]cyt), which in turn activate many proteins involved in signaling pathways, from yeast to humans [2]. Thanks to easy manipulation, rapid growth, genetic amenability and with many genes bearing resemblance with higher eukaryotic genes, the yeast
Heavy metals represent a constant threat to clean environments as they are constantly released in the course of various anthropogenic activities (Figure 1), both industrial (mining, electroplating, smelting, metallurgical processes, nanoparticles, unsafe agricultural practices) and domestic (sewage and waste, metal corrosion), all in the context of rapid industrialization and urbanization [25]. Heavy metals as contaminants are included in the category of persistent pollutants, because they cannot be destroyed or degraded. Being natural components of the earth crust, the environmental contamination becomes serious when heavy metals have the possibility to leach into surface or underground water, or undergo atmospheric deposition and metal evaporation from the water resources [26, 27, 28]. The ultimate threat imposed by the spread of heavy metals into the environment is their accumulation in the living organisms (Figure 1) via the food chain [29], inducing serious illnesses in animals and humans [30, 31, 32, 33, 34].
Some heavy metals (Co2+, Cu2+, Fe2+, Mn2+, Ni2+, Mo2+, and Zn2+) are essential for life, contributing to various biochemical and physiological functions in the living organisms. The nutritional requirements of these elements are generally low and they must be present in food in trace concentrations [35]. However, excessive exposure to higher concentrations is deleterious, representing a threat to living organisms [36]. Other heavy metals (Ag+, Cd2+, Pb2+, Hg2+) are not essential for life and have no established biological roles, but they are highly toxic because they compete with the essential metals for their biological targets or they simply bind nonspecifically to biomolecules; these metals are able to induce toxicity at low doses [37]. Essential or not, the hazardous heavy metals such as Cd2+, Co2+, Cu2+, Mn2+, Ni2+, Pb2+, Zn2+ are known to be major threats to the environment [38]. The molecular mechanisms involved in heavy metal transport and homeostasis have been intensively studied in
2. Calcium transport and homeostasis in S. cerevisiae
Intracellular calcium ions are important second messengers in all organisms, including yeast. The mechanisms involved in calcium transport and homeostasis in
Changes in the cell environment are signaled by a sudden increase in [Ca2+]cyt which can be a consequence of either external Ca2+ influx via the Cch1p/Mid1p channel on the plasma membrane [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 56], release of vacuolar Ca2+ into the cytosol through the vacuole-located Ca2+ channel Yvc1p [18, 57], or both (Figure 2). After delivering the message, the level of [Ca2+]cyt is restored to the normal very low levels through the action of Ca2+ pumps and exchangers. Thus, the Ca2+-ATPase Pmc1p [58, 59] and a vacuolar Ca2+/H+ exchanger Vcx1p [60, 61] independently transport [Ca2+]cyt into the vacuole, while Pmr1p, the secretory Ca2+-ATPase, pumps [Ca2+]cyt into endoplasmic reticulum (ER) and Golgi along with Ca2+ extrusion from the cell [62, 63]. These responses are mediated by the universal Ca2+ sensor protein calmodulin that can bind and activate calcineurin, which inhibits at the post-transcriptional level the function of Vcx1p [60, 64, 65] and induces the expression of
3. Aequorin, a transgenic molecular tool for detecting [Ca2+]cyt changes in S. cerevisiae
As a second messenger, Ca2+ triggers a variety of cascade responses by temporarily activating Ca2+-binding components of signaling pathways which can lead either to adaptation to the environmental changes or to cell death [71]. To determine the [Ca2+]cyt fluctuations during cell exposure to environmental changes, it is necessary to have an system capable to detect the sudden and transient elevations in [Ca2+]cyt. This was made possible by the isolation of aequorin, a Ca2+-binding photoprotein, isolated from the luminescent jellyfish,
The expression of cDNA for apoaequorin in yeast cells and subsequent regeneration of apoaequorin into aequorin provide a noninvasive, nontoxic and effective method to detect the transient variations in yeast [Ca2+]cyt [76]. The yeast strains to be analysed must express the
In
4. Correlations between calcium and heavy metal exposure as seen in S. cerevisiae cells
When grown in media contaminated with heavy metals, the yeast cell wall is the first to get in contact with the surplus cations present in the cell surroundings. If the contamination is not excessive, the cations would probably get stuck at this level, due to the mannoproteins that compose the outer layer of the cell wall (alongside of β-glucans and chitin) which are heavily phosphorylated and carboxylated, decorating the cell façade with a negatively charged shield prone to bind to positively charged species, such as the metal cations [83]. Excess metal ions which escape the negatively charged groups on the cell wall surface penetrate the porous cell wall and reach the membrane to exert their toxic effect by disrupting the lipid bilayer or by assaulting the membrane transporters.
Several heavy metals (Co2+, Cu2+, Fe2+, Mn2+, Ni2+, and Zn2+) are essential for life in their ionic forms, acting mainly as cofactors for a variety of enzymes. They are necessary only in minute amounts inside the cell (hence their denomination as “trace” elements); if their concentration goes beyond the physiological threshold they become toxic by nonspecifically binding to any biomolecule bearing a negative charge or a metal-chelator fragment. The bipolar nature of trace metals determined the development of intricate cellular systems dedicated to their uptake, buffering, sequestration, intracellular trafficking, compartmentalization and excretion. As in many other directions of study,
To have any chance of survival under heavy metal stress, the cell needs to be one step ahead of the “villain” ions and to get prepared for defense by using various strategies. The attempts to understand the role of calcium in preparing the yeast cell to resist the heavy metal attack are summarized in the following sections.
4.1. Cd2+
Cd2+ is one of the most studied non-essential heavy metals as it is a global environmental pollutant present in soil, air, water, and food, representing a major hazard to human health [92]. External Cd2+ was shown to unequivocally induce the [Ca2+]cyt elevations in
It had been suggested that Cd2+ toxicity was a direct consequence of Cd2+ accumulation in the ER and that Cd2+ does not inhibit disulphide bond formation (which could account for the lack of response in the case of Zn2+ and Hg2+) but perturbs calcium metabolism. Cd2+ activates the calcium channel Cch1/Mid1 under low external Ca2+, which also contributes to Cd2+ entry into the cell [93]; the protective effect of Ca2+ may be the result of competitive uptake between the two cations at the plasma membrane. In this line of evidence, it was shown that excess concentration of extracellular Ca2+ attenuates the Cd2+-induced ER stress [94]. It was determined that divalent Cd2+ and Ca2+ have very similar physical properties, with ionic radii of Ca2+ (0.97 Å) and Cd2+ (0.99 Å) giving similar charge/radius ratios, meaning that these ions are able to exert strong electrostatic forces on biological macromolecules [95]. Under such circumstances, the Cd2+-induced aequorin luminescence observed could also be the result of aequorin binding to Cd2+ instead of Ca2+. This was not the case though: when measuring the Cd2+ accumulation in yeast cells, it was revealed that the Cd2+-induced aequorin luminescence occurred significantly faster than the Cd2+ uptake, indicating that the luminescence produced was the result of increase in [Ca2+]cyt [23].
4.2. Cu2+
Cu2+ is one of the most important essential metals: a variety of enzymes require copper as a cofactor for electron transfer reactions [96]. Nevertheless, when in excess, Cu2+ is very toxic in the free form because of its ability to produce free radicals when cycling between oxidized Cu2+ and reduced Cu+. Studies correlating Ca2+ with Cu2+ toxicity in yeast are scarce, but it had been known that the inhibitory effect of Cu2+ on glucose-dependent H+ efflux from
It was found that the cell exposure to high Cu2+-induced broad Ca2+ waves into the cytosol which were accompanied by elevations in cytosolic Ca2+ with patterns that were influenced by the Cu2+ concentration but also by the oxidative state of the cell [18, 24]. When Ca2+ channel deletion mutants were used, it was revealed that the main contributor to the cytosolic Ca2+ pool under Cu2+ stress was the vacuolar Ca2+ channel, Yvc1p, also activated by the Cch1p-mediated Ca2+ influx (Figure 6). Using yeast mutants defective in the Cu2+ transport across the plasma membrane, it was found that the Cu2+-dependent Ca2+ elevation could correlate with the accumulated metal, but also with the Cu2+ − induced oxidative stress and the overall oxidative status. Moreover, it was revealed that Cu2+ and H2O2 acted in synergy to induce Ca2+-mediated responses to external stress [24]. Interestingly, other redox active metals such as Mn2+ or Fe2+ were inactive in inducing [Ca2+]cyt waves ([23], unpublished observations), probably because these metals are less redox-reactive than the Cu2+/Cu+ couple (Figure 6D) under aerobic conditions [98].
4.3. Mn2+
High manganese failed to elicit Ca2+ elevations irrespective of the magnitude of the insult applied ([23]; unpublished observations). The response was monitored over a wide range of concentrations (from the quasi-physiological 0.5 mM to the super lethal 50 mM) and times (up to 60 min of exposure). Of all the cations, Mn2+ is the closest to Ca2+ in terms of ionic radius and charge. This similarity is so relevant that Mn2+ effectively supports yeast cell-cycle progression in place of Ca2+ [99]. This similarity probably renders the cell irresponsive to high concentrations of an otherwise toxic metal. A more subtle Mn2+-Ca2+ interplay exists though, being manifested at several levels [41]. For example, high Mn2+ is controlled by calcineurin/Crz1p-regulated Pmr1p and Pun1p [100]. Importantly, the tolerance of yeast cells to Mn2+ is related to both Pmr1p and Vcx1p [41, 64, 65, 101] two determinants of maintaining low [Ca2+]cyt by transporting the ions to the vacuole and Golgi/ER, respectively [60, 61, 62, 63]. The Ca2+-dependent response to Mn2+ surplus seems to be induced not by external Mn2+, but by the cations accumulated inside the cell. For example, it was found that internal Mn2+ can be redistributed by calcium-stimulated vesicle trafficking [102].
4.4. Fe2+
Fe2+ toxicity can be the result of direct ionic effect, but the indirect effect of catalyzing Fenton reactions, in which highly reactive oxygen species arise, represents the main concern raised by Fe2+ surplus. As in the case of Mn2+, excess Fe2+ did not elicit sudden elevations in [Ca2+]cyt upon exposure [23]. It had been reported that yeast strains lacking the components of the Cch1p/Mid1p plasma membrane channel were hypersensitive to Fe2+. When measuring the relative Ca2+ accumulation, it was noted that iron stress also increased the residual Ca2+ uptake in the
4.5. Other metals
The surplus of heavy metals such as Ni2+, Co2+, Pb2+, Hg2+, and Ag+ did not have the ability to rapidly induce elevations in [Ca2+]cyt. In some cases, (Ni2+ and Co2+) exogenous Ca2+ alleviated the toxicity of the metal ions, but this effect was rather related to the inhibition of Co2+ or Ni2+ uptake by Ca2+ [103].
5. Concluding remarks
In this chapter, we attempted to highlight the studies made in
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