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

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.

Suppression of statin effectiveness by copper and zinc in yeast and human cells

“…9, 12, 13 We established that at the concentration of statin and for the period of treatment we employed, petite formation did not occur (Supplementary Fig. 1).…”

“…Mevalonic acid produced a strong rescue effect, in accord with previous studies. 9, 10 Ergosterol did not rescue, likely because it is sparingly soluble in water and therefore not bioavailable to yeast after dilution into the culture. Indeed, reports of the effectiveness of ergosterol in the rescue of yeast treated with sterol synthesis inhibitors are conflicting, likely for this reason.…”

“…9, 10 Statin treatment produces dose-dependent growth inhibition in yeast. By combining exposure of yeast to a library of 52 metabolites along with lovastatin treatment, we found that the divalent metal ions zinc, copper and manganese alleviated statin-mediated growth inhibition.…”

The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway

“…Polymorphisms in the mitochondrial ribosome recycling factor EF-G2mt/MEF2 increase atorvastatin toxicity in yeast and mammalian cells (34), suggesting that mitochondria prone to homeostatic failure are extra sensitive to statins. This is consistent with a number of studies showing the mitochondria to be the main site of action of the noncholesterol effects of statins (3).…”

Morphological and Molecular Differentiation of Sporidiobolus johnsonii ATCC 20490 and Its Coenzyme Q10 Overproducing Mutant Strain UF16

“…Most of the mutant colonies on atorvastatin containing plate were mucoid and pale in color. The toxicity of atorvastatin to yeast cells has been reported [43] hence mutant colonies on the atorvastatin containing plate were picked up and further maintained on plain YM agar plates without atorvastatin.…”