Metolazone upregulates mitochondrial chaperones and extends lifespan in Caenorhabditis elegans.

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.

journal_name

Biogerontology

journal_title

Biogerontology

authors

Ito A,Zhao Q,Tanaka Y,Yasui M,Katayama R,Sun S,Tanimoto Y,Nishikawa Y,Kage-Nakadai E

doi

10.1007/s10522-020-09907-6

subject

Has Abstract

pub_date

2021-02-01 00:00:00

pages

119-131

issue

1

eissn

1389-5729

issn

1573-6768

pii

10.1007/s10522-020-09907-6

journal_volume

22

pub_type

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