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.
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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.
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
Tunneling nanotubes (TNTs) are open actin- and membrane-based channels, connecting remote cells and allowing direct transfer of cellular material (e.g. vesicles, mRNAs, protein aggregates) from the cytoplasm to the cytoplasm. Although they are important especially, in pathological conditions (e.g. cancers, neurodegenerative diseases), their precise composition and their regulation were still poorly described. Here, using a biochemical approach allowing to separate TNTs from cell bodies and from extracellular vesicles and particles (EVPs), we obtained the full composition of TNTs compared to EVPs. We then focused on two major components of our proteomic data, the CD9 and CD81 tetraspanins, and further investigated their specific roles in TNT formation and function. We show that these two tetraspanins have distinct non-redundant functions: CD9 participates in stabilizing TNTs, whereas CD81 expression is required to allow the functional transfer of vesicles in the newly formed TNTs, possibly by regulating docking to or fusion with the opposing cell.
