Targeting Copper Homeostasis Improves Functioning of vps13Δ Yeast Mutant Cells, a Model of VPS13-Related Diseases

Abstract

Ion homeostasis is crucial for organism functioning, and its alterations may cause diseases. For example, copper insufficiency and overload are associated with Menkes and Wilson’s diseases, respectively, and iron imbalance is observed in Parkinson’s and Alzheimer’s diseases. To better understand human diseases, Saccharomyces cerevisiae yeast are used as a model organism. In our studies, we used the vps13Δ yeast strain as a model of rare neurological diseases caused by mutations in VPS13A-D genes. In this work, we show that overexpression of genes encoding copper transporters, CTR1, CTR3, and CCC2, or the addition of copper salt to the medium, improved functioning of the vps13Δ mutant. We show that their mechanism of action, at least partially, depends on increasing iron content in the cells by the copper-dependent iron uptake system. Finally, we present that treatment with copper ionophores, disulfiram, elesclomol, and sodium pyrithione, also resulted in alleviation of the defects observed in vps13Δ cells. Our study points at copper and iron homeostasis as a potential therapeutic target for further investigation in higher eukaryotic models of VPS13-related diseases.

Yeast as a Model to Find New Drugs and Drug Targets for VPS13-Dependent Neurodegenerative Diseases

“…There are not many reports on iron or copper dyshomeostasis in VPS13-dependent diseases or metal ion contribution in their pathogenesis so far [169]. Finding FET4, encoding iron transporter, and CTR3, encoding copper transporter, as suppressors of vps13∆ [41,170] provides a hint that metal disturbances could contribute to the pathogenesis of VPS13dependent diseases and opens the possibility of discovering new drugs and drug targets aimed at the normalisation of these disturbances. For this purpose, a chemical suppressor screen (as depicted in Figure 3) of compounds from the Prestwick Chemical Library, a collection of 1280 drugs (most of which have been approved for use in humans), was performed and resulted in the identification of luteolin and tolcapone as vps13∆ chemical suppressors [41].…”

“…A potential target of copper, iron and luteolin action could be the biosynthesis of complex sphingolipids, which are important membrane components during SDS stress. Figure from Soczewka et al (2021) [170] was supplemented and modified.…”

Application of Metabolomics in the Study of Starvation-Induced Autophagy in Saccharomyces cerevisiae: A Scoping Review

“…Baker's yeast Saccharomyces cerevisiae has been used as research models for diseases such as neurodegenerative disorders [22], aging [23], lifespan [24] oxidative stress [25], and autophagy [26]. The genes in S. cerevisiae are highly homologous to those in humans [27,28], and the simplicity of manipulating the genes [14,29,30] and nutrition [31,32] of this shortlived yeast make it a favorable eukaryotic representative.…”

Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases

“…Soczewka et al [10] and Wardaszka et al [11] further characterized the importance of VPS13 proteins for cell physiology by studying the yeast vps13∆ mutant devoid of the yeast Vps13 protein. A simple phenotype, i.e., the hypersensitivity of the vps13∆ mutant to the commonly used detergent sodium dodecyl sulphate (SDS), allowed the authors to use the power of yeast genetics to discover changes in copper homeostasis, in addition to the already described changes in calcium [12] and iron [13] homeostasis.…”

“…The first way shown in this Special Issue is overexpression of the RCN2 gene, encoding the Rcn2 protein, which causes partial downregulation of calcineurin activity, a key calciumdependent phosphatase, by inhibiting only the subset of catalytic complexes [11]. The second way is the increase in the cellular level of copper ions via simple supplementation with copper salts, treatment with copper ionophores, or genetic manipulation, resulting in an increase in copper uptake [10]. This is an interesting finding since copper ion homeostasis has already been shown to be affected in Alzheimer's and Parkinson's diseases and copper ionophores are in clinical trials [14].…”