Atorvastatin-induced cell toxicity in yeast is linked to disruption of protein isoprenylation

Sylvie Callegari, Ross McKinnon, Stuart Andrews, Miguel de Barros Lopes

    Research output: Contribution to journalArticle

    11 Citations (Scopus)

    Abstract

    Statins, used to treat hypercholesterolemia, are one of the most frequently prescribed drug classes in the developed world. However, a significant proportion of users suffer symptoms of myotoxicity, and currently, the molecular mechanisms underlying myotoxicity remain ambiguous. In this study, Saccharomyces cerevisiae was exploited as a model system to gain further insight into the molecular mechanisms of atorvastatin toxicity. Atorvastatin-treated yeast cells display marked morphological deformities, have reduced cell viability and are highly vulnerable to perturbed mitochondrial function. Supplementation assays of atorvastatin-treated cells reveal that both loss of viability and mitochondrial dysfunction occur as a consequence of perturbation of the sterol synthesis pathway. This was further investigated by supplementing statin-treated cells with various metabolites of the sterol synthesis pathway that are believed to be essential for cell function. Ergosterol, coenzyme Q and a heme precursor were all ineffective in the prevention of statin-induced mitochondrial disruption and cell death. However, the addition of geranylgeranyl pyrophosphate and farnesyl pyrophosphate significantly restored cell viability, although these did not overcome petite induction. This highlights the pleiotropic nature of statin toxicity, but has established protein prenylation disruption as one of the principal mechanisms underlying statin-induced cell death in yeast.

    Original languageEnglish
    Pages (from-to)188-198
    Number of pages11
    JournalFEMS YEAST RESEARCH
    Volume10
    Issue number2
    DOIs
    Publication statusPublished - Mar 2010

    Keywords

    • Atorvastatin
    • Mitochondrial damage
    • Myalgia
    • Protein prenylation
    • Yeast

    Fingerprint Dive into the research topics of 'Atorvastatin-induced cell toxicity in yeast is linked to disruption of protein isoprenylation'. Together they form a unique fingerprint.

  • Cite this