Simvastatin reduces ergosterol levels, inhibits growth and causes loss of mtDNA inCandida glabrata

Abstract

Statins are widely used for lowering cholesterol levels through their action on 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Yeasts use HMG-CoA reductase for the same enzymatic step as humans, but in yeasts the main end-product of the pathway is ergosterol rather than cholesterol. We considered that insights into the effects of statins in humans could be gained by examination of the effects of simvastatin on the petite-positive yeast Candida glabrata. Simvastatin was found to inhibit growth, and this was associated with lower ergosterol levels. As simvastatin-treated cultures of yeast were passaged, the frequencies of petite cells (respiratory-deficient yeast mutants with deletions in the mitochondrial genome) increased with time and with simvastatin concentration. DNA staining of the petite mutants showed that they were devoid of mtDNA, suggesting a defect in the maintenance of mtDNA. These observations in C. glabrata may provide further insights into the molecular effects of statins in humans undergoing treatment for hypercholesterolemia. In addition, if C. glabrata is a valid model for studying statin treatments, it would be very useful for the preliminary screening of agents to reduce statin side-effects.

Simvastatin Inhibits Candida albicans Biofilm In Vitro

“…An inhibitor of squalene synthetase, an intermediate step in the cholesterol pathway, blocked staphyloxanthin production and attendant virulence in Staphylococcus aureus (43). Lovastatin-mediated growth inhibition has been reported for several pathogenic and nonpathogenic yeasts and one mold (31,39,44). For example, 100 M simvastatin or atorvastatin inhibited growth of four Candida species (C. albicans, tropicalis, glabrata, and parapsilosis) as well as Aspergillus fumigatus (36).…”

Biological consequences of statins in Candida species and possible implications for human health

“…His screening showed that 17 genes involved in sterol uptake and/or transport are also involved in mitochondrial functions [32]. Mutants deficient in ergosterol biosynthesis showed swollen and clumped mitochondria [27]. All these point to a significant interconnection between the mevalonate pathway and mtDNA maintenance in the yeast cell.…”

“…Furthermore, unlike regular spontaneous petites that undergo specific deletions in their mitochondrial genome and amplify the remaining DNA (so-called ρ − petites), statin-induced petites are totally devoid of mtDNA and are designated ρ o . DAPI (4 ,6-diamidino-2-phenylindole) staining of cellular DNA of petites showed that only nuclear DNA was present in such cells (see Figures 2B and 2C) [27].…”

“…Loss of mtDNA from cells via unequal segregation could lead to loss of mtDNA in daughter cells, or defective mtDNA replication could cause the loss of mtDNA. Membraneperturbing agents such as ethanol can result in ergosterol reduction and associated petite induction in S. cerevisiae [27]. It has previously been shown that the replication of mtDNA is membrane-associated [28].…”

“…Ergosterol reduction [23,27] Cholesterol reduction [18,40] Loss of respiratory function; petite induction; mtDNA loss [23,27,39] Loss of membrane potential; swelling of the mitochondria; inhibition of electron transport chain and mitochondrial oxidation [19,37] Loss of respiratory growth;…”