Back to Search
Start Over
Respiratory deficiency in yeast mevalonate kinase deficient may explain MKD-associate metabolic disorder in humans.
- Source :
-
Current genetics [Curr Genet] 2018 Aug; Vol. 64 (4), pp. 871-881. Date of Electronic Publication: 2018 Jan 27. - Publication Year :
- 2018
-
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.
- Subjects :
- Gene Expression Regulation, Fungal
Genome, Fungal
Humans
Mevalonate Kinase Deficiency metabolism
Mevalonate Kinase Deficiency pathology
Mutation
Phosphotransferases (Alcohol Group Acceptor) deficiency
Saccharomyces cerevisiae enzymology
Saccharomyces cerevisiae Proteins genetics
Terpenes metabolism
Transcription Factors genetics
Ubiquinone genetics
Ubiquinone metabolism
Mevalonate Kinase Deficiency genetics
Phosphotransferases (Alcohol Group Acceptor) genetics
Respiration genetics
Saccharomyces cerevisiae genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0983
- Volume :
- 64
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Current genetics
- Publication Type :
- Academic Journal
- Accession number :
- 29374778
- Full Text :
- https://doi.org/10.1007/s00294-018-0803-2