Statins interfere with the attachment of S. cerevisiae mtDNA to the inner mitochondrial membrane

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.

Keywords:

• Statins
• ergosterol
• cholesterol
• mitochondrial DNA
• myopathy

Acknowledgements

We thank Silvia Francisci and Arianna Montanari for providing the C25T strain and Dr. Luigi Gatta and Dr. Andrea Morelli for scientific discussion. T.R. thanks Laura Frontali for constant support on mitochondrial research and for sharing the invaluable experience on this field.

Disclosure statement

The authors report no declarations of interest.

Additional information

Funding

This research was supported by Ateneo Sapienza, Sapienza University of Rome, Italy, grant number RP11715C541D4BFF and RP11816418C88AAC to MMB, grant number RM11816413C50F4B to RN and TR; Israel Ministry of Science and Technology (MOST)- Italy Ministry of Foreign Affairs (MAECI), grant number 3–9022 to EP and TR; Israel Science Foundation, grant number 162/17 for EP.