Abstract
The 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme of the mevalonate pathway for the synthesis of cholesterol in mammals (ergosterol in fungi), is inhibited by statins, a class of cholesterol lowering drugs. Indeed, statins are in a wide medical use, yet statins treatment could induce side effects as hepatotoxicity and myopathy in patients. We used Saccharomyces cerevisiae as a model to investigate the effects of statins on mitochondria. We demonstrate that statins are active in S.cerevisiae by lowering the ergosterol content in cells and interfering with the attachment of mitochondrial DNA to the inner mitochondrial membrane. Experiments on murine myoblasts confirmed these results in mammals. We propose that the instability of mitochondrial DNA is an early indirect target of statins.
Highlights
Cholesterol is a vital component of cell membranes, essential for the synthesis of steroid hormones, bile acids, and vitamin D, but high cholesterol levels are associated with an elevated risk of cardiovascular diseases
We previously demonstrated that ketoconazole, which blocks the ergosterol biosynthetic pathway downstream the hydroxy3-methylglutaryl coenzyme A (HMG-CoA) reductase, reduced the ergosterol content in yeast cells and induced the loss of mitochondrial DNA; this phenomenon is coupled with a re-localisation of Erg[27] enzyme from Lipid Droplets (LDs) to Endoplasmic Reticulum (ER)[19]
Yeast is recognised as a good model to study the cellular mechanisms of mitochondrial human diseases and S. cerevisiae is unique among yeasts because it is able to survive with non-functional mitochondria[17]
Summary
Cholesterol is a vital component of cell membranes, essential for the synthesis of steroid hormones, bile acids, and vitamin D, but high cholesterol levels are associated with an elevated risk of cardiovascular diseases. HMG-CoA is the target of statins[4], the most prescribed drug class for lowering elevated LDL-cholesterol, generally effective and well tolerated; patients can experience muscle adverse effects such as myopathy[5,6]. The activity of statins was investigated previously in the yeast Candida glabrata[13] and in Saccharomyces cerevisiae[14]; the yeast S. cerevisiae is an excellent unicellular model to gain insights into human diseases[15] in particular, those resulting from impaired mitochondrial function[16,17,18], because S. cerevisiae is able, utilising fermentable carbon sources to survive without mitochondrial respiration. We previously demonstrated that ketoconazole, which blocks the ergosterol biosynthetic pathway downstream the HMG-CoA reductase, reduced the ergosterol content in yeast cells and induced the loss of mitochondrial DNA; this phenomenon is coupled with a re-localisation of Erg[27] enzyme from Lipid Droplets (LDs) to Endoplasmic Reticulum (ER)[19]. Upon statins treatment, we observed a reduction of mitochondrial DNA copy number associated with an impaired differentiation capacity
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