Loss of HMG-CoA reductase in C. elegans causes defects in protein prenylation and muscle mitochondria

HMG-CoA reductase is the rate-limiting enzyme in the mevalonate pathway and the target of cholesterol-lowering statins. We characterized the C. elegans hmgr-1(tm4368) mutant, which lacks HMG-CoA reductase, and show that its phenotypes recapitulate that of statin treatment, though in a more severe fo...

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Bibliographic Details
Published in:PloS one 2014-06, Vol.9 (2), p.e100033
Main Authors: Ranji, Parmida, Rauthan, Manish, Pitot, Christophe, Pilon, Marc
Format: Article
Language:English
Subjects:
ACTIVATION
Animals
Biology and life sciences
Caenorhabditis elegans - genetics
Caenorhabditis elegans - physiology
Caenorhabditis elegans - ultrastructure
Caenorhabditis elegans Proteins - genetics
Caenorhabditis elegans Proteins - metabolism
CAENORHABDITIS-ELEGANS
Cell and Molecular Biology
Cell- och molekylärbiologi
Cholesterol
Defects
Enzymes
Gene Deletion
GERM-CELL MIGRATION
Hydroxymethylglutaryl CoA Reductases - genetics
Hydroxymethylglutaryl CoA Reductases - metabolism
Hydroxymethylglutaryl-CoA reductase
Kinases
MEVALONATE PATHWAY
Mevalonic acid
Mevalonic Acid - metabolism
Mitochondria
Mitochondria, Muscle - genetics
Mitochondria, Muscle - pathology
Mitochondria, Muscle - ultrastructure
Mitochondrial DNA
Muscles
Nematodes
Physiological aspects
Protein Prenylation
Reproduction
Research and Analysis Methods
Signal Transduction
Statins
Transcription Factors - metabolism
UPR
Worms
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Summary:HMG-CoA reductase is the rate-limiting enzyme in the mevalonate pathway and the target of cholesterol-lowering statins. We characterized the C. elegans hmgr-1(tm4368) mutant, which lacks HMG-CoA reductase, and show that its phenotypes recapitulate that of statin treatment, though in a more severe form. Specifically, the hmgr-1(tm4368) mutant has defects in growth, reproduction and protein prenylation, is rescued by exogenous mevalonate, exhibits constitutive activation of the UPRer and requires less mevalonate to be healthy when the UPRmt is activated by a constitutively active form of ATFS-1. We also show that different amounts of mevalonate are required for different physiological processes, with reproduction requiring the highest levels. Finally, we provide evidence that the mevalonate pathway is required for the activation of the UPRmt.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0100033