Manganese transport and trafficking: lessons learned from Saccharomyces cerevisiae.

Manganese represents an essential trace element that is accumulated and utilized by virtually all forms of life. This redox active metal is a key cofactor for a wide range of metalloenzymes, including oxidases and dehydrogenases, DNA and RNA polymerases, kinases, decarboxylases, and sugar transferases (11, 25). In addition to serving as an essential nutrient, manganese can also be toxic. In humans, exposure to manganese can cause severe neurological damage, leading to a Parkinsonian-like disorder known as “manganism” (3, 4, 46, 59, 69). While the biological importance of manganese has long been recognized, there is scarce understanding regarding the mechanisms of manganese homeostasis. Virtually every compartment of the cell contains one or more enzymes that require manganese for activity, and in order for manganese to reach said targets, the ion must overcome a number of obstacles. Lipid bilayer membranes must be crossed at both the cell surface and at organelles. In addition, the metal must evade the detoxification factors designed to sequester or eliminate manganese from the cell. Because manganese is potentially toxic, the ion is not likely to diffuse in the cell unattended, but, rather, is handled in a carefully controlled fashion by manganese homeostasis proteins. Such homeostasis factors include cell surface and intracellular manganese transporters and putative manganese chaperones that collectively guide the metal down a designated trafficking pathway, ultimately culminating in the activation of manganese enzymes. To date, only a few of the players involved in the network of manganese trafficking have been identified, and these have largely been revealed through molecular genetic studies of the baker’s yeast, Saccharomyces cerevisiae. This review shall highlight pathways of manganese homeostasis and trafficking that are operative under three distinct metabolic conditions: (i) manganese replete or “physiological” conditions when manganese is amply available for activation of manganese-requiring enzymes; (ii) manganese starvation stress, including the cellular response to compensate for low manganese availability; and (iii) manganese surplus or manganese toxicity, including the transport pathways and mechanisms of detoxification. Where applicable, references shall be made to analogous pathways described for humans, including potential implications for disease. (Physiological, as used in item i above, means nonstressed laboratory growth conditions, i.e., when manganese is amply available to activate manganese enzymes but is not at surplus levels at which toxicity might ensue. However, “physiological” conditions or the natural growth state for S. cerevisiae in the wild might be more akin to manganese starvation conditions.)