Manganese, whose name is derived from a Greek word for magic, is an essential trace element that is required by organisms across every kingdom of life.1 The magic of manganese lies not only in its ability to transform itself into an effector for a diverse range of redox and nonredox functions but also in its ability to appear and disappear from a variety of locations within a cell. Regarding the former, decades of chemical, biochemical, and biophysical characterization of manganese-containing complexes have revealed much about how primary and secondary coordination spheres temper the reactivity and function of the metal center.2,3 However, regarding the latter, the cellular transport and trafficking of manganese, much of the mystery persists.4–6
A diverse array of metalloproteins require manganese for function, including oxidoreductases, DNA and RNA poly-merases, peptidases, kinases, decarboxylases, and sugar transferases, which are present in a variety of cellular locales, such as the nucleus, mitochondria, cytosol, Golgi, and vacuole.3 Yet it is not completely clear how cells manage to import appropriate amounts of environmental manganese, transport the metal to the correct intracellular compartments, and distribute it to relevant biomacromolecules.4–6 Matters may be further complicated by environmental stresses that could lead to under- or overexposure of cells to manganese; too little manganese may inactivate manganese-requiring biological processes, whereas too much manganese is toxic.3–6 The latter is underscored by manganism, a Parkin-son’s disease-like condition in which overexposure to manganese leads to severe neurological damage.7–12 In such instances where cells are manganese stressed, either through deficiency or surplus, living systems are obligated to respond through the concerted regulation of manganese cell surface and intracellular transporters, as well as any putative manganese chaperones, so as to maintain healthy intracellular concentrations of the metal and correctly appropriate manganese to its cognate protein ligands.4–6
Much of our current, albeit limited understanding of manganese homeostatic mechanisms has been elucidated through molecular genetic studies of the budding yeast, Saccharomyces cerevisiae. As such, this review will largely focus on global manganese homeostatic pathways operative in the eukaryotic cell of S. cerevisiae, with references being made to analogous pathways in metazoans where applicable. Specifically, this review will highlight the mechanisms by which cell surface and intracellular manganese transporters import and distribute manganese, as well as how these homeostatic mechanisms respond to manganese deficiency or surplus.
The manner in which cells mediate the uptake and distribution of manganese is dependent on the exposure of environmental manganese to the cell. As depicted in Figure 1, manganese exposure lies on a continuum between two environmental extremes, manganese deficiency and surplus, with manganese sufficiency occupying a place in the continuum between the two extremes.6 The range of intra-cellular manganese levels that constitute manganese sufficiency is quite large, nearly 2 orders of magnitude. In various studies done, yeast were seen to accumulate between 2–100 nmol of manganese/(10 × 109 cells), or 0.04–2.0 mM manganese (assuming a single yeast cell has a volume of 50 femtoliters), without any impact on cell growth.13–18 However, at levels below or above this, the stresses of manganese deficiency and manganese toxicity ensue, setting off a series of responses aimed at normalizing manganese levels. In general, cells respond to such manganese stress by upregulating or downregulating cell surface and intra-cellular transport systems. As described in detail below, regulation of manganese transport in yeast does not involve any known transcriptional pathway,6,13,19 such as those described for transporters of copper, zinc, and iron.20 Instead, all the known manganese regulatory pathways in yeast occur at the post-translational level through changes in transporter protein localization and turnover. In this review, we shall provide an overview of the various manganese transport systems in S. cerevisiae, how they function under diverse cellular conditions, and how certain transporters are regulated in response to manganese stress.