1. Metolazone upregulates mitochondrial chaperones and extends lifespan in Caenorhabditis elegans
- Author
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Quichi Zhao, Yoshikazu Nishikawa, Ai Ito, Eriko Kage-Nakadai, Simo Sun, Yoshihiko Tanimoto, Masumi Yasui, Yoichiro Tanaka, and Rina Katayama
- Subjects
0301 basic medicine ,Aging ,ved/biology.organism_classification_rank.species ,Longevity ,Green fluorescent protein ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Metolazone ,Mitochondrial unfolded protein response ,Animals ,Humans ,Model organism ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,Ubiquitins ,biology ,ved/biology ,Endoplasmic reticulum ,biology.organism_classification ,Cell biology ,030104 developmental biology ,chemistry ,Chaperone (protein) ,biology.protein ,Geriatrics and Gerontology ,Gerontology ,030217 neurology & neurosurgery ,HeLa Cells ,Transcription Factors - Abstract
Accumulating studies have argued that the mitochondrial unfolded protein response (UPRmt) is a mitochondrial stress response that promotes longevity in model organisms. In the present study, we screened an off-patent drug library to identify compounds that activate UPRmt using a mitochondrial chaperone hsp-6::GFP reporter system in Caenorhabditis elegans. Metolazone, a diuretic primarily used to treat congestive heart failure and high blood pressure, was identified as a prominent hit as it upregulated hsp-6::GFP and not the endoplasmic reticulum chaperone hsp-4::GFP. Furthermore, metolazone specifically induced the expression of mitochondrial chaperones in the HeLa cell line. Metolazone also extended the lifespan of worms in a atfs-1 and ubl-5-dependent manner. Notably, metolazone failed to increase lifespan in worms with knocked-down nkcc-1. These results suggested that metolazone activates the UPRmt across species and prolongs the lifespan of C. elegans.
- Published
- 2020