Regulation of Cation Balance in Saccharomyces cerevisiae

All living organisms require nutrient minerals for growth and have developed mechanisms to acquire, utilize, and store nutrient minerals effectively. In the aqueous cellular environment, these elements exist as charged ions that, together with protons and hydroxide ions, facilitate biochemical reactions and establish the electrochemical gradients across membranes that drive cellular processes such as transport and ATP synthesis. Metal ions serve as essential enzyme cofactors and perform both structural and signaling roles within cells. However, because these ions can also be toxic, cells have developed sophisticated homeostatic mechanisms to regulate their levels and avoid toxicity. Studies in Saccharomyces cerevisiae have characterized many of the gene products and processes responsible for acquiring, utilizing, storing, and regulating levels of these ions. Findings in this model organism have often allowed the corresponding machinery in humans to be identified and have provided insights into diseases that result from defects in ion homeostasis. This review summarizes our current understanding of how cation balance is achieved and modulated in baker’s yeast. Control of intracellular pH is discussed, as well as uptake, storage, and efflux mechanisms for the alkali metal cations, Na⁺ and K⁺, the divalent cations, Ca²⁺ and Mg²⁺, and the trace metal ions, Fe²⁺, Zn²⁺, Cu²⁺, and Mn²⁺. Signal transduction pathways that are regulated by pH and Ca²⁺ are reviewed, as well as the mechanisms that allow cells to maintain appropriate intracellular cation concentrations when challenged by extreme conditions, i.e., either limited availability or toxic levels in the environment.IN addition to the major components of organic molecules, i.e., carbon, nitrogen, hydrogen, and oxygen, living organisms require multiple chemical elements, termed nutrient minerals, for growth. In the aqueous cellular environment, these elements exist as charged ions that, together with protons and hydroxide ions, facilitate biochemical reactions. Charged ions, which cannot diffuse across lipid bilayers, also provide the raw material to establish electrochemical gradients that drive cellular processes such as ATP synthesis. Potassium ions help balance negative charge inside cells and activate critical metabolic processes such as protein translation. Trace elements, such as zinc, copper, iron, and manganese, are critical determinants of protein structure and serve as essential enzyme cofactors. Calcium performs structural, enzymatic, and signaling roles within cells. All of these essential elements can also be toxic. Thus, cells must be able to acquire, utilize, and store nutrient minerals effectively, but have also developed sophisticated homeostatic mechanisms to regulate their levels and avoid toxicity. Genetic studies in yeast have identified key components responsible for acquiring, utilizing, storing, and regulating levels of these ions. Furthermore, because many of these proteins are highly conserved, yeast serves as an excellent model to identify the corresponding machinery in humans and understand diseases that result from defects in ion homeostasis. A genome-wide study measured levels of 13 elements in >4000 yeast deletion strains grown in rich medium to establish the yeast “ionome.” Relatively few mutations (212) were found to significantly perturb the ionome, revealing that robust mechanisms exist to compensate for loss of a single component of ion homeostasis (Eide et al. 2005). However, the vast majority of the 212 mutations identified altered the level of more than one element, and subsets of elements covaried, illustrating the cooperative nature of the regulatory networks that control intracellular ion levels. These studies also highlighted the critical role that intracellular organelles, particularly the vacuole and the mitochondria, play in ion regulation.This chapter reviews our current understanding of how cation balance is achieved and regulated in baker’s yeast. Starting with monovalent cations and proceeding to divalent metal ions, the role of each cation is briefly reviewed, with particular emphasis on current knowledge of its uptake, storage, and efflux mechanisms. Where appropriate, roles for cation in signal transduction pathways are also discussed.