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Review
. 2019 Jul 17;10(7):545.
doi: 10.3390/genes10070545.

Yeast as a Tool for Deeper Understanding of Human Manganese-Related Diseases

Louise Thines  1 , Antoine Deschamps  1 , Jiri Stribny  1 , Pierre Morsomme  2
Affiliations
Review

Yeast as a Tool for Deeper Understanding of Human Manganese-Related Diseases

Louise Thines et al. Genes (Basel). .

Abstract

The biological importance of manganese lies in its function as a key cofactor for numerous metalloenzymes and as non-enzymatic antioxidant. Due to these two essential roles, it appears evident that disturbed manganese homeostasis may trigger the development of pathologies in humans. In this context, yeast has been extensively used over the last decades to gain insight into how cells regulate intra-organellar manganese concentrations and how human pathologies may be related to disturbed cellular manganese homeostasis. This review first summarizes how manganese homeostasis is controlled in yeast cells and how this knowledge can be extrapolated to human cells. Several manganese-related pathologies whose molecular mechanisms have been studied in yeast are then presented in the light of the function of this cation as a non-enzymatic antioxidant or as a key cofactor of metalloenzymes. In this line, we first describe the Transmembrane protein 165-Congenital Disorder of Glycosylation (TMEM165-CDG) and Friedreich ataxia pathologies. Then, due to the established connection between manganese cations and neurodegeneration, the Kufor-Rakeb syndrome and prion-related diseases are finally presented.

Keywords: Friedreich ataxia; Kufor-Rakeb; TMEM165-CDG; antioxidant; cofactor; disease; manganese; neurodegeneration; prion diseases; yeast.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Suggested manganese transport pathways in the yeast Saccharomyces cerevisiae. The currently-identified yeast transporters proposed to transport Mn2+ are: Smf1p, a plasma membrane Natural Resistance-Associated Macrophage Protein (NRAMP) transporter; Pho84p, a plasma membrane phosphate transporter that can transport Mn2+; Pmr1p, a Golgi Ca2+ and Mn2+-transporting P-type ATPase; Gdt1p, a Golgi Ca2+ and Mn2+ secondary transporter; Atx2p, a putative Mn2+ transporter at the Golgi; Cod1p, a Mn2+-transporting P-type ATPase at the endoplasmic reticulum (ER); Smf2p, a NRAMP transporter that localizes in intracellular vesicles; Ypk9p, a P-type ATPase importing manganese in the vacuole; Ccc1p, a vacuolar Mn2+ and Fe2+ transporter. These transporters ensure proper maintenance of the manganese concentrations in the physiological range and activity of the Mn2+-dependent enzymes: the superoxide dismutase Sod2p in the mitochondrial matrix and mannosyltransferases (Mnn) in the Golgi lumen. The arrows represent the putative direction of transport of Mn2+, while the rectangles and circles correspond to secondary transporters and ATPases, respectively.
Figure 2
Figure 2
Manganese-related molecular mechanisms beyond the development of Transmembrane protein 165-Congenital Disorder of Glycosylation (TMEM165-CDG) (A) and of Friedreich ataxia (B). (A) Disease-causing mutations within the human gene coding for the Golgi-localized protein TMEM165 are thought to cause its mislocalization or to affect its transport capacity, both leading to disturbed manganese homeostasis in the Golgi lumen. In this compartment, the altered bioavailability of manganese for the Mn2+-dependent β-1,4-galactosyltransferase (β-1,4-gal) would affect its enzymatic function and lead to the production of hypo-galactosylated N-glycans. (B) Friedreich ataxia is characterized by a decreased production of the mitochondrial frataxin and by iron overload. This metal overaccumulation is, in turn, thought to induce, in yeast, vacuolar targeting of the protein Smf2p, that plays a key role in manganese dispatching within the cell, which, in turn, leads to cellular manganese deficiency. Both manganese deficiency and iron overload drive the formation of the inactive apo- and Fe-bound superoxide dismutase 2 (SOD2), thereby altering oxidative stress protection and leading to decreased activities of the Fe-S enzymes.
Figure 3
Figure 3
Mn2+-related molecular pathways associated with the development of two neurodegenerative diseases: the Kufor-Rakeb syndrome (A) and prion-related disorders (B). (A) Specific mutations within the human gene ATP13A2 have been shown to induce misfolding of the α-syn protein and its subsequent neurotoxic aggregation that leads to the formation of Lewy bodies in human neurons. In parallel, mutated ATP13A2 has been shown to directly disturb manganese homeostasis, thereby establishing a connection between genetics (α-syn and ATP13A2) and environmental (unbalanced manganese exposure) causes of neurodegeneration. (B) The human protein PrP interacts, in its functional isoform (PrPC), with copper, and also with manganese. This interaction with manganese has been suggested to induce the conversion of PrPC to its proteinase-resistant counterpart PrPSc. In this form, PrP forms neurotoxic aggregates, thereby leading to the prion-disease associated symptoms.
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