ArticleProceedings of the National Academy of Sciences of the United States of America2013
The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
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Who cites it
82 citing papers in PubMed, 134 citations in OpenAlex.
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- ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.Nature communications · 2026Article
- Forward genetics ineLife · 2025Article
- Mild activation of the mitochondrial unfolded protein response increases lifespan without increasing resistance to stress.Open biology · 2025Article
- Unzipping the defense: a comprehensive review on bZIP transcription factors inFrontiers in cellular and infection microbiology · 2025Review
- Germline status and micronutrient availability regulate a somatic mitochondrial quality control pathway via short-chain fatty acid metabolism.bioRxiv : the preprint server for biology · 2024Article
- Mitochondrial recovery by the UPRSeminars in cell & developmental biology · 2024Review
- Multifaceted roles of mitochondria in wound healing and chronic wound pathogenesis.Frontiers in cell and developmental biology · 2023Review
- Mitochondrial dysfunction, aging, and the mitochondrial unfolded protein response in Caenorhabditis elegans.Genetics · 2022Review
- The UPRmt preserves mitochondrial import to extend lifespan.The Journal of cell biology · 2022Article
- Mitochondrial thioredoxin system is required for enhanced stress resistance and extended longevity in long-lived mitochondrial mutants.Redox biology · 2022Article
- Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation.Pharmaceutics · 2022Review
- A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response.eLife · 2022Article
- Box C/D small nucleolar ribonucleoproteins regulate mitochondrial surveillance and innate immunity.PLoS genetics · 2022Article
- The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations.Frontiers in molecular neuroscience · 2022Review
- Mild mitochondrial impairment enhances innate immunity and longevity through ATFS-1 and p38 signaling.EMBO reports · 2021Article
22 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 1 institution in 1 country.
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Abstract
Statins are cholesterol-lowering drugs that inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the synthesis of cholesterol via the mevalonate pathway. This pathway also produces coenzyme Q (a component of the respiratory chain), dolichols (important for protein glycosylation), and isoprenoids (lipid moieties responsible for the membrane association of small GTPases). We previously showed that the nematode Caenorhabditis elegans is useful to study the noncholesterol effects of statins because its mevalonate pathway lacks the sterol synthesis branch but retains all other branches. Here, from a screen of 150,000 mutagenized genomes, we isolated four C. elegans mutants resistant to statins by virtue of gain-of-function mutations within the first six amino acids of the protein ATFS-1, the key regulator of the mitochondrial unfolded protein response that includes activation of the chaperones HSP-6 and HSP-60. The atfs-1 gain-of-function mutants are also resistant to ibandronate, an inhibitor of an enzyme downstream of HMG-CoA reductase, and to gliotoxin, an inhibitor acting on a subbranch of the pathway important for protein prenylation, and showed improved mitochondrial function and protein prenylation in the presence of statins. Additionally, preinduction of the mitochondrial unfolded protein response in wild-type worms using ethidium bromide or paraquat triggered statin resistance, and similar observations were made in Schizosaccharomyces pombe and in a mammalian cell line. We conclude that statin resistance through maintenance of mitochondrial homeostasis is conserved across species, and that the cell-lethal effects of statins are caused primarily through impaired protein prenylation that results in mitochondria dysfunction.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.