Simvastatin reduces ergosterol levels, inhibits growth and causes loss of mtDNA in Candida 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.
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Many studies suggested that statins can cause mitochondrial dysfunction and stimulate the generation of ROS production.
“Many studies suggested that statins can cause mitochondrial dysfunction and stimulate the generation of ROS production [50,54].”
From Pitavastatin Calcium Confers Fungicidal Properties to Fluconazole by Inhibiting Ubiquinone Biosynthesis and Generating Reactive Oxygen Species (2024) · cites this paper as [54]
Supplementation with ergosterol or cholesterol reduced the antifungal effect of statins.
“This assumption is confirmed by the observation that supplementation with ergosterol or cholesterol reduced the antifungal effect of statins [20,25,26] , and that C. albicans transformed from the yeast cell form to the”
From Statins as antifungal agents (2011) · cites this paper as [26]
MIC definition may account for differences; some liquid-culture works defined MIC as the drug dose reducing growth by 50% by optical density, while others defined it as the minimal concentration with no visible growth.
“For comparison purposes, the MIC definition may also account for differences.Some works, normally referring to liquid cultures, described MIC as the drug dose at which growth became reduced by 50%, as witnessed by optical density measurements.32,40 Nevertheless, there are authors that defined MIC as herein applied, i.e. the minimal concentration at which no visible growth occurred.3,21”
Slow sterol uptake and statin-induced depletion of other mevalonate pathway endproducts may explain why sole ergosterol supplementation failed to rescue growth.
“A slow sterol uptake as well as the deleterious statin-induced depletion of many other endproducts from the mevalonate pathway may account for the rescue fail by the sole ergosterol supplementation.40”
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“Many studies suggested that statins can cause mitochondrial dysfunction and stimulate the generation of ROS production [50,54].”
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- Authors
- Westermeyer, C., & Macreadie, I. G.
- Affiliations
- Commonwealth Scientific and Industrial Research Organisation (AU)
- Corresponding author
- Macreadie, Ian G.
- ORCID
- Macreadie, Ian G.
- Venue
- FEMS Yeast Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-05
- Volume
- 7
- Issue
- 3
- Pages
- 436-441
- ISSN
- 1567-1356 (ISSN-L)
- 1567-1364
- OpenAlex
- W2074530271
- Cited by
- 73
- References
- 30
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 7 · 2020: 6 · 2019: 8 · 2018: 3 · 2017: 1 · 2015: 3 · 2014: 2 · 2013: 7 · 2012: 3
- FWCI
- 1.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- FEMS Yeast Research (publishedVersion)
- PubMed (publishedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Figshare (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- simvastatin, statins, Candida glabrata, ergosterol, HMG-CoA reductase, petite mutants, mitochondrial DNA loss, mitochondrial DNA maintenance, yeast growth inhibition, statin adverse effects, hypercholesterolemia, yeast model
- MeSH terms
- DNA, Mitochondrial, Ergosterol, Humans, Hypercholesterolemia, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Candida glabrata
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