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

Angela Cirigliano; Antonia Amelina; Beatrice Biferali; Alberto Macone; Chiara Mozzetta; Michele Maria Bianchi; Mattia Mori; Bruno Botta; Elah Pick; Rodolfo Negri; Teresa Rinaldi

doi:10.1080/14756366.2019.1687461

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

J Enzyme Inhib Med Chem. 2020 Dec;35(1):129-137. doi: 10.1080/14756366.2019.1687461.

Authors

Angela Cirigliano¹, Antonia Amelina¹, Beatrice Biferali^{1

2}, Alberto Macone^{3

4}, Chiara Mozzetta^{1

2}, Michele Maria Bianchi¹, Mattia Mori⁵, Bruno Botta⁶, Elah Pick⁷, Rodolfo Negri^{1

2}, Teresa Rinaldi^{1

3}

Affiliations

¹ Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Rome, Italy.
² Institute of Molecular Biology and Pathology, CNR, Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Rome, Italy.
³ Pasteur Institute-Cenci Bolognetti Foundation, Rome, Italy.
⁴ Institute of Molecular Biology and Pathology, CNR, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza University of Rome, Rome, Italy.
⁵ Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
⁶ Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, Rome, Italy.
⁷ Department of Biology and Environment, Faculty of Natural Sciences, University of Haifa at Oranim, Tivon, Israel.

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; cholesterol; ergosterol; mitochondrial DNA; myopathy.

MeSH terms

DNA, Mitochondrial / chemistry
DNA, Mitochondrial / metabolism*
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemistry
Hydroxymethylglutaryl-CoA Reductase Inhibitors / metabolism*
Mitochondria / metabolism*
Mitochondrial Membranes / chemistry
Mitochondrial Membranes / metabolism*
Saccharomyces cerevisiae / chemistry*

Substances

DNA, Mitochondrial
Hydroxymethylglutaryl-CoA Reductase Inhibitors

Grants and 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.