2.4.2. Manganese Toxicity

In the model yeast *S. cerevisiae*, excessive Mn2+ can overrun homeostatic systems and create a toxic ionic imbalance that negatively impacts survival rate [104,285,286]. Expression profiles show that high levels of Mn2+ down-regulate genes associated to histidine proteins (*HTB2*, *HTA1*, *HTA2*, *HTB1*, and *HHF*) that are compulsory in chromatin assembly chromosome functioning, and interface in this functioning can end in cell cycle arrest [94,95,114,287]. Filamentous fungi are often studied for their lignin degradation properties which focus on how Mn2+ impacts manganese peroxidase activity, but there is a lack of knowledge on how excess Mn2+ can be toxic towards this activity [96–98]. Due to the reliability of much of the lignin degrading properties on manganese peroxidase in many white-rot fungi, effects of Mn2+ over accumulation should be further investigated [96–98]. In some cases, toxicity can be avoided by resistance mechanisms.

#### 2.4.3. Manganese Tolerance and Resistance

As with other metals, Mn2+ resistance is usually contingent upon homeostatic systems. In *S*. *cerevisiae*, several genes involved in resistance emanate from mutations. *MNR1* (also known as *HUM1* and *VCX1*), encodes a vacuolar H+/Ca2+ antiporter, but has been implicated in Mn2+ resistance [125,288,289]. A single nucleotide alteration may affect Mnr1 function and result in increased Mn2+ sequestration to the vacuole [125,289,290]. A mutation in *PHO84* is also implicated in Mn2+ resistance, where *pho84*∆ mutants have increased resistance, likely due to the acquired inability to import and accumulate excess Mn2+ [67]. In filamentous fungi, Diss et al. elucidated potential resistance mechanisms through *P. chrysosporium,* where it was demonstrated that *PcPho84*∆ mutants increase Mn2+ resistance, as well as expression of *PcMNT*, which is likely to engage in Mn2+export activity [68].

Up to this point, metals that serve as essential nutrients have been reviewed. In recent years, there has been an increase in studies on the usage of metals with no nutritional purpose, but which serve as antimicrobial agents, such as silver. This increase gives cause for further investigation into how these metals are metabolized and their intracellular functioning.
