PGAM5 promotes lasting FoxO activation after developmental mitochondrial stress and extends lifespan in Drosophila
- Buck Institute for Research on Aging, United States
- Buck Institute For Research On Aging, United States
Abstract
The mitochondrial unfolded protein response (UPRmt) has been associated with long lifespan across metazoans. In C. elegans, mild developmental mitochondrial stress activates UPRmt reporters and extends lifespan. We show that similar developmental stress is necessary and sufficient to extend Drosophila lifespan, and identify Phosphoglycerate Mutase 5 (PGAM5) as a mediator of this response. Developmental mitochondrial stress leads to activation of FoxO, via Apoptosis Signal-regulating Kinase 1 (ASK1) and Jun-N-terminal Kinase (JNK). This activation persists into adulthood and induces a select set of chaperones, many of which have been implicated in lifespan extension in flies. Persistent FoxO activation can be reversed by a high protein diet in adulthood, through mTORC1 and GCN-2 activity. Accordingly, the observed lifespan extension is prevented on a high protein diet and in FoxO-null flies. The diet-sensitivity of this pathway has important implications for interventions that seek to engage the UPRmt to improve metabolic health and longevity.
Article and author information
Author details
Funding
National Institute on Aging (R01 AG028127)
- Yanyan Qi
- Rebeccah Riley
- Heinrich Jasper
American Federation for Aging Research (Breakthroughs in Gerontology award)
- Heinrich Jasper
Alfred Benzon Foundation (Postdoctoral fellowship)
- Martin Borch Jensen
National Institute on Aging (R01 AG050104)
- Yanyan Qi
- Rebeccah Riley
- Heinrich Jasper
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Utpal Banerjee, University of California, Los Angeles, United States
Version history
- Received: March 17, 2017
- Accepted: September 8, 2017
- Accepted Manuscript published: September 11, 2017 (version 1)
- Version of Record published: September 26, 2017 (version 2)
- Version of Record updated: April 10, 2018 (version 3)
Copyright
© 2017, Borch Jensen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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PGAM5 promotes lasting FoxO activation after developmental mitochondrial stress and extends lifespan in Drosophila
eLife 6:e26952.
https://doi.org/10.7554/eLife.26952
Further reading
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- Cell Biology
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