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

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.

The lack of non-steroid isoprenoids causes oxidative stress in patients with mevalonic aciduria.

Mevalonic aciduria belongs to a group of rare inherited metabolic disorders related to cholesterol biosynthesis. The pathogenesis of mevalonic aciduria is not clear, although the cause is known - a genetic defect leading to a deficiency in mevalonate kinase activity. The lack of non-steroid isoprenoids in patients with mevalonic aciduria might cause oxidative stress due to a decreased production of endogenous antioxidants including ubiquinone 10, selenoproteins and glutathione peroxidase. The Moosmann-Behl hypothesis of statin-induced muscular and neuronal damage mediated by oxidative stress might explain at least partially the pathogenesis of mevalonic aciduria. Studies focusing on the role of oxidative stress in patients suffering from disorders in cholesterol biosynthesis are needed to support adjuvant antioxidative treatment.