Respiratory deficiency in yeast mevalonate kinase deficient may explain MKD-associate metabolic disorder in humans

Abstract

Mevalonate kinase deficiency (MKD) an orphan drug rare disease affecting humans with different clinical presentations, is still lacking information about its pathogenesis; no animal or cell model mimicking the genetic defect, mutations at MVK gene, and its consequences on the mevalonate pathway is available. Trying to clarify the effects of MVK gene impairment on the mevalonate pathway we used a yeast model, the erg12-d mutant strain Saccharomyces cerevisiae (orthologous of MKV) retaining only 10% of mevalonate kinase (MK) activity, to describe the effects of reduced MK activity on the mevalonate pathway. Since shortage of isoprenoids has been described in MKD, we checked this observation using a physiologic approach: while normally growing on glucose, erg12-d showed growth deficiency in glycerol, a respirable carbon source, that was not rescued by supplementation with non-sterol isoprenoids, such as farnesol, geraniol nor geranylgeraniol, produced by the mevalonate pathway. Erg12-d whole genome expression analysis revealed specific downregulation of RSF2 gene encoding general transcription factor for respiratory genes, explaining the absence of growth on glycerol. Moreover, we observed the upregulation of genes involved in sulphur amino acids biosynthesis that coincided with the increasing in the amount of proteins containing sulfhydryl groups; upregulation of ubiquinone biosynthesis genes was also detected. Our findings demonstrated that the shortage of isoprenoids is not the main mechanism involved in the respiratory deficit and mitochondrial malfunctioning of MK-defective cells, while the scarcity of ubiquinone plays an important role, as already observed in MKD patients.

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“…This is generally thought to create a problem for developing antifungal compounds, while minimizing potential toxicity and adverse effects. Fungal models are used to understand human biology and disease conditions (Botstein and Fink 2011; Hartwell 2004; Krobitsch and Lindquist 2000; Menne et al 2007; Santos et al 2018; Sun et al 2016; van Pel et al 2013), and the reverse is also possible—in some instances the field of medical mycology might be able to exploit the similarities between fungal and mammalian cells, to build on the knowledge of cellular processes and compounds that are of interest in non-infectious human diseases. One such case is mitochondrial fission, the process by which mitochondria divide.…”

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