Manganese transport and trafficking: Lessons learned from Saccharomyces cerevisiae

Manganese is a biologically important metal that is both a nutrient and a toxic element. Cells must therefore carefully control the uptake and trafficking of this ion. While the picture of manganese homeostasis is far from complete, many advances have been made with the baker's yeast, S. cerevisiae. Under nonstressful conditions, when manganese is amply available, the uptake and intracellular dissemination of the metal rely heavily on Smf2p, a Nramp manganese transporter. Emerging downstream of Smf2p are at least two manganese trafficking pathways, one that escorts manganese to the Golgi, where the transporting ATPase Pmr1p delivers manganese to sugar transferases, and a separate pathway that delivers manganese to mitochondrial SOD2 (Fig. 1). The mitochondrial transporter for manganese is still unknown, yet the metal is made available to SOD2 through the action of Mtmlp, a member of the mitochondrial carrier family (Fig. 1). When cells are faced with manganese starvation, they respond by increasing levels of both Nramp manganese transporters, Smflp and Smf2p. Normally, Smf1p and Smf2p are largely degraded in the vacuole to minimize uptake of toxic metals. But with manganese starvation, the transporters fail to arrive at the vacuole and instead localize to the cell surface and intracellular vesicles to enhance uptake and distribution of the metal (Fig. 2). The mechanism by which cells sense manganese and respond by shifting localization of the Nramp transporters is an area of current investigation. At the opposite end of the spectrum, i.e., when cells are exposed to toxic levels of manganese, the Smfp transporters are essentially nonexistent. However, cells still accumulate the metal by way of manganese-phosphate complexes taken up by the Pho84p phosphate transporter. The excess manganese is then either sequestered in the vacuole or eliminated from the cell by way of Pmr1p and the secretory pathway (Fig. 3). The role of the secretory pathway in manganese homeostasis and detoxification is likely to be conserved among eukaryotes and is of particular relevance in cases of manganese neurotoxicity in humans.