The mevalonate pathway is the primary target of the cholesterol-lowering drugs statins, some of the most widely prescribed medicines of all time. The pathway’s enzymes not only catalyze the synthesis of cholesterol but also of diverse metabolites such as mitochondrial electron carriers and isoprenyls. Recently, it has been shown that one type of mitochondrial stress response, the UPRmt, can protect yeast, Caenorhabditis elegans, and cultured human cells from the deleterious effects of mevalonate pathway inhibition by statins. The mechanistic basis for this protection, however, remains unknown. Using C. elegans, we found that the UPRmt does not directly affect the levels of the statin target HMG-CoA reductase, the rate-controlling enzyme of the mevalonate pathway in mammals. Instead, in C. elegans the UPRmt upregulates the first dedicated enzyme of the pathway, HMG-CoA synthase (HMGS-1). A targeted RNA interference (RNAi) screen identified two UPRmt transcription factors, ATFS-1 and DVE-1, as regulators of HMGS-1. A comprehensive analysis of the pathway’s enzymes found that, in addition to HMGS-1, the UPRmt upregulates enzymes involved with the biosynthesis of electron carriers and geranylgeranylation intermediates. Geranylgeranylation, in turn, is requisite for the full execution of the UPRmt 3response. Thus, the UPRmt acts in at least three coordinated, compensatory arms to upregulate specific branches of the mevalonate pathway, thereby alleviating mitochondrial stress. We propose that statin-mediated inhibition of the mevalonate pathway blocks this compensatory system of the UPRmt and consequentially impedes mitochondrial homeostasis. This effect is likely one of the principal bases for the adverse side effects of statins.
Bibliographical noteFunding Information:
Some strains were provided by the CGC, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). We are grateful to Cole Haynes (The University of Massachusetts, Amherst, MA), David L. Baillie (Simon Fraser University, Burnaby, BC, Canada), Matt Kaeberlein (University of Washington, Seattle, WA), Paul W. Sternberg (Caltech, Pasadena, CA), Shane L. Rea (University of Texas, Houston, TX), and Sivan Henis-Korenblit (Bar-Ilan U, Ramat Gan, Israel) for C. elegans strains. We thank Yoram Gercheman, Elah Pick, Benjamin Trabelsi, and Shamsuzzama (all from the University of Haifa, Haifa, Israel) for reagents and assistance with the analysis of qPCR results. We thank Limor Broday (Tel-Aviv University, Tel Aviv, Israel), Ayelet Lamm, and Benjamin Podbilewicz (The Technion, Haifa, Israel) for providing reagents and laboratory space. We are grateful to Vinci Au, Pegah Abyaneh, Mark Edgley, and Donald G. Moerman (The University of British Columbia, Vancouver, BC, Canada) for generating, by the CRISPR-Cas9 method, the hmgs-1 deletion allele. The generation of this deletion allele was supported by the CIHR (Canadian Institute for Health Research) grant to Donald G. Moerman. This work was supported
by the Israel Science Foundation (ISF) grants 41764 and 41765 to A.S.
© 2018, Genetics Society of America. All rights reserved.
- Mevalonate pathway
- Mitochondrial stress
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