Metolazone upregulates mitochondrial chaperones and extends lifespan in Caenorhabditis elegans.

Biogerontology
Ai ItoEriko Kage-Nakadai

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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Citations

Apr 9, 2021·Frontiers in Cell and Developmental Biology·Kai-Lieh LinTsu-Kung Lin
Aug 10, 2021·Disease Models & Mechanisms·Peter A KroppAndy Golden
Sep 30, 2021·Life Science Alliance·Sonja K SooJeremy M Van Raamsdonk

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