Current Genetics

, Volume 64, Issue 4, pp 871–881 | Cite as

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

  • Manuella Maria Silva Santos
  • Carolina Elsztein
  • Rafael Barros De Souza
  • Sérgio de Sá Leitão PaivaJr
  • Jaqueline Azevêdo Silva
  • Sergio Crovella
  • Marcos Antonio De MoraisJr
Original Article


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.


Isoprenoids Gene expression Microarray Respiratory metabolism Yeast 



This work has been partially supported by the RC42/11 from IRCCS Burlo Garofolo (Trieste, Italy) and by the research fund of the Federal University of Pernambuco.

Supplementary material

294_2018_803_MOESM1_ESM.xlsx (180 kb)
Table S1. List of differentially expressed genes in four conditions: Erg12-d glycerol relative to wild type glycerol, wild type glycerol relative to wild type Glucose, Erg12-d glycerol relative to Erg12-d glucose and Erg12-d glucose relative to wild type glucose (XLSX 180 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Manuella Maria Silva Santos
    • 1
    • 2
  • Carolina Elsztein
    • 1
    • 3
  • Rafael Barros De Souza
    • 1
    • 4
  • Sérgio de Sá Leitão PaivaJr
    • 5
  • Jaqueline Azevêdo Silva
    • 2
    • 6
  • Sergio Crovella
    • 2
    • 6
  • Marcos Antonio De MoraisJr
    • 1
    • 2
  1. 1.Interdepartmental Research Group in Metabolic EngineeringFederal University of PernambucoRecifeBrazil
  2. 2.Department of GeneticsFederal University of PernambucoRecifeBrazil
  3. 3.Department of virology/CPqAMOswaldo Cruz FundationRecifeBrazil
  4. 4.Institute for Biologial SciencesUniversity of PernambucoRecifeBrazil
  5. 5.Laboratory of Bioinformatics and Evolutionary BiologyFederal Rural University PernambucoRecifeBrazil
  6. 6.Laboratory of Immunopathology Keizo AsamiFederal University of PernambucoRecifeBrazil

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