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Mitochondrial unfolded protein response transcription factor ATFS-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways
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Mitochondrial unfolded protein response transcription factor ATFS-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways
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Journal Article
Mitochondrial unfolded protein response transcription factor ATFS-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways
2018
Overview
Background
The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway activated by disruption of proteostasis in the mitochondria. This pathway has been proposed to influence lifespan, with studies suggesting that mitoUPR activation has complex effects on longevity.
Results
Here, we examined the contribution of the mitoUPR to the survival and lifespan of three long-lived mitochondrial mutants in
Caenorhabditis elegans
by modulating the levels of ATFS-1, the central transcription factor that mediates the mitoUPR. We found that
clk-1
,
isp-1
, and
nuo-6
worms all exhibit an ATFS-1-dependent activation of the mitoUPR. While loss of
atfs-1
during adulthood does not affect lifespan in any of these strains, absence of
atfs-1
during development prevents
clk-1
and
isp-1
worms from reaching adulthood and reduces the lifespan of
nuo-6
mutants. Examining the mechanism by which deletion of
atfs-1
reverts
nuo-6
lifespan to wild-type, we find that many of the transcriptional changes present in
nuo-6
worms are mediated by ATFS-1. Genes exhibiting an ATFS-1-dependent upregulation in
nuo-6
worms are enriched for transcripts that function in stress response and metabolism. Consistent, with this finding, loss of
atfs-1
abolishes the enhanced stress resistance observed in
nuo-6
mutants and prevents upregulation of multiple stress response pathways including the HIF-1-mediated hypoxia response, SKN-1-mediated oxidative stress response and DAF-16-mediated stress response.
Conclusions
Our results suggest that in the long-lived mitochondrial mutant
nuo-6
activation of the mitoUPR causes
atfs-1-
dependent changes in the expression of genes involved in stress response and metabolism, which contributes to the extended longevity observed in this mutant. This work demonstrates that the mitoUPR can modulate multiple stress response pathways and suggests that it is crucial for the development and lifespan of long-lived mitochondrial mutants.
Publisher
BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
Subject
/ Aging
/ Animals
/ ATFS-1
/ Biomedical and Life Sciences
/ Caenorhabditis elegans - genetics
/ Caenorhabditis elegans - physiology
/ Caenorhabditis elegans Proteins - genetics
/ Caenorhabditis elegans Proteins - metabolism
/ Enzymes
/ Genes
/ Genomes
/ Hypoxia
/ Lifespan
/ Mitochondrial Proteins - genetics
/ Mitochondrial Proteins - metabolism
/ Mitochondrial unfolded protein response
/ Mutants
/ Mutation
/ Oxidative Stress - physiology
/ Proteins
/ Transcription Factors - genetics
/ Transcription Factors - metabolism
/ Worms
