Journal
CELL REPORTS
Volume 21, Issue 6, Pages 1481-1494Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.10.038
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Funding
- NIH Office of Research Infrastructure Programs [P40 OD010440]
- NIH (National Institute on Aging) [R01AG026647]
- Ellison Medical Foundation
- Daniel F. and Ada L. Rice Foundation
- ALS Association
- BBSRC [BB/P005535/1]
- [R01AG047182]
- BBSRC [BB/P005535/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/P005535/1] Funding Source: researchfish
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In Caenorhabditis elegans, the programmed repression of the heat shock response (HSR) accompanies the transition to reproductive maturity, leaving cells vulnerable to environmental stress and protein aggregation with age. To identify the factors driving this event, we performed an unbiased genetic screen for suppressors of stress resistance and identified the mitochondrial electron transport chain (ETC) as a central regulator of the age-related decline of the HSR and cytosolic proteostasis. Mild downregulation of ETC activity, either by genetic modulation or exposure to mitochondria-targeted xenobiotics, maintained the HSR in adulthood by increasing HSF-1 binding and RNA polymerase II recruitment at HSF-1 target genes. This resulted in a robust restoration of cytoplasmic proteostasis and increased vitality later in life, without detrimental effects on fecundity. We propose that low levels of mitochondrial stress regulate cytoplasmic proteostasis and healthspan during aging by coordinating the long-term activity of HSF-1 with conditions preclusive to optimal fitness.
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