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The UPRmt Protects Caenorhabditis elegans from Mitochondrial Dysfunction by Upregulating Specific Enzymes of the Mevalonate Pathway

Olga Oks, Shany Lewin, Irina Langier Goncalves and Amir Sapir
Genetics Early online March 29, 2018; https://doi.org/10.1534/genetics.118.300863
Olga Oks
University of Haifa
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Shany Lewin
University of Haifa
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Irina Langier Goncalves
University of Haifa
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Amir Sapir
University of Haifa
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  • For correspondence: amirsapir1@gmail.com
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Abstract

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, C. 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 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 response. 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.

  • Mitochondrial stress
  • UPRmt
  • Mevalonate pathway
  • Statins
  • C. elegans
  • Cholesterol
  • Received February 27, 2018.
  • Revision received March 23, 2018.
  • Accepted March 23, 2018.
  • Copyright © 2018, Genetics
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Volume 208 Issue 4, April 2018

Genetics: 208 (4)

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The UPRmt Protects Caenorhabditis elegans from Mitochondrial Dysfunction by Upregulating Specific Enzymes of the Mevalonate Pathway

Olga Oks, Shany Lewin, Irina Langier Goncalves and Amir Sapir
Genetics Early online March 29, 2018; https://doi.org/10.1534/genetics.118.300863
Olga Oks
University of Haifa
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Shany Lewin
University of Haifa
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Irina Langier Goncalves
University of Haifa
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Amir Sapir
University of Haifa
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  • For correspondence: amirsapir1@gmail.com
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Citation

The UPRmt Protects Caenorhabditis elegans from Mitochondrial Dysfunction by Upregulating Specific Enzymes of the Mevalonate Pathway

Olga Oks, Shany Lewin, Irina Langier Goncalves and Amir Sapir
Genetics Early online March 29, 2018; https://doi.org/10.1534/genetics.118.300863
Olga Oks
University of Haifa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shany Lewin
University of Haifa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Irina Langier Goncalves
University of Haifa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Amir Sapir
University of Haifa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: amirsapir1@gmail.com

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