Metolazone upregulates mitochondrial chaperones and extends lifespan in Caenorhabditis elegans
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RESEARCH ARTICLE
Metolazone upregulates mitochondrial chaperones and extends lifespan in Caenorhabditis elegans Ai Ito . Quichi Zhao . Yoichiro Tanaka . Masumi Yasui . Rina Katayama . Simo Sun . Yoshihiko Tanimoto . Yoshikazu Nishikawa . Eriko Kage-Nakadai
Received: 28 August 2020 / Accepted: 11 November 2020 Ó Springer Nature B.V. 2020
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 hsp6::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 hsp6::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
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10522-020-09907-6) contains supplementary material, which is available to authorized users. A. Ito Q. Zhao Y. Tanaka M. Yasui R. Katayama S. Sun Y. Tanimoto Y. Nishikawa E. Kage-Nakadai (&) Faculty of Human Life Science, Department of Food and Nutrition, Osaka City University, Sugimoto 3-3-138 Sumiyoshi-ku, Osaka 558-8585, Japan e-mail: [email protected] E. Kage-Nakadai The OCU Advanced Research Institute for Natural Science and Technology, Osaka City University, Osaka 558-8585, Japan
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. Keywords UPRmt Off-patent drug Metolazone Longevity C. elegans
Introduction Aging is an intricate process involving a decline in cellular and physiological processes. Among the many contributors to aging, such as genetic predisposition, programmed senescence, and DNA damage, mitochondria have been implicated as one of the key players. Impairment of mitochondrial integrity and function activates a transcriptional response regulated by mitochondrial-to-nuclear communication known as the mitochondrial unfolded protein response (UPRmt). UPRmt promotes the recovery of mitochondrial fusion and fission, as well as mitochondrial DNA replication, thereby facilitating the survival of the cell (Haynes and Ron 2010; Melber and Haynes 2018; Schulz and Haynes 2015; Shpilka and Haynes 2018). The molecular mechanisms of UPRmt were first elucidated in Caenorhabditis elegans. ATFS-1 (activating transcription factor associated with stress) is one of the central transcription factors required for
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Biogerontology
UPRmt activation in C. elegans (Haynes et al. 2010; Runkel et al.
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