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.
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Acknowledgements
We thank the Caenorhabditis Genetics Center (CGC), which is funded by the National Institutes of Health (NIH) Office of Research Infrastructure Programs (P40 OD010440), for providing the C. elegans strains. This work was supported by Osaka City University Strategic Research Grant 2018 and 2020 (to E.K.-N.) and the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 18K10998 (to E.K.-N.). This work was also supported by the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Funding
This work was funded by Osaka City University Strategic Research Grant 2018 and 2020 (to E.K.-N.) and the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 18K10998 (to E.K.-N.).
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EKN designed the study. AI carried out the lifespan assays and RNAi experiments. QZ carried out the chemical screens. YTNK, MY, RK, and SS carried out the lifespan assays, measurements of body size and brood size, and determination of pharyngeal pumping rates. YTNK and YTNM carried out the cell culture experiments and performed data analyses. EKN wrote the manuscript. EKN and YN supervised the project. All the authors have read and approved the manuscript.
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Ito, A., Zhao, Q., Tanaka, Y. et al. Metolazone upregulates mitochondrial chaperones and extends lifespan in Caenorhabditis elegans. Biogerontology 22, 119–131 (2021). https://doi.org/10.1007/s10522-020-09907-6
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DOI: https://doi.org/10.1007/s10522-020-09907-6