1. Cell Biology
  2. Chromosomes and Gene Expression
Download icon

PGAM5 promotes lasting FoxO activation after developmental mitochondrial stress and extends lifespan in Drosophila

  1. Martin Borch Jensen  Is a corresponding author
  2. Yanyan Qi
  3. Rebeccah Riley
  4. Liya Rabkina
  5. Heinrich Jasper  Is a corresponding author
  1. Buck Institute for Research on Aging, United States
  2. Buck Institute For Research On Aging, United States
Research Article
  • Cited 27
  • Views 2,855
  • Annotations
Cite this article as: eLife 2017;6:e26952 doi: 10.7554/eLife.26952

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

  1. Martin Borch Jensen

    Buck Institute for Research on Aging, Novato, United States
    For correspondence
    martinborchjensen@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
  2. Yanyan Qi

    Buck Institute for Research on Aging, Novato, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Rebeccah Riley

    Buck Institute for Research on Aging, Novato, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Liya Rabkina

    Buck Institute for Research on Aging, Novato, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Heinrich Jasper

    Buck Institute For Research On Aging, Novato, United States
    For correspondence
    hjasper@buckinstitute.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6014-4343

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

  1. Utpal Banerjee, University of California, Los Angeles, United States

Publication history

  1. Received: March 17, 2017
  2. Accepted: September 8, 2017
  3. Accepted Manuscript published: September 11, 2017 (version 1)
  4. Version of Record published: September 26, 2017 (version 2)
  5. 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.

Metrics

  • 2,855
    Page views
  • 630
    Downloads
  • 27
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Zdravka Daneva et al.
    Research Article Updated

    Pannexin 1 (Panx1), an ATP-efflux pathway, has been linked with inflammation in pulmonary capillaries. However, the physiological roles of endothelial Panx1 in the pulmonary vasculature are unknown. Endothelial transient receptor potential vanilloid 4 (TRPV4) channels lower pulmonary artery (PA) contractility and exogenous ATP activates endothelial TRPV4 channels. We hypothesized that endothelial Panx1–ATP–TRPV4 channel signaling promotes vasodilation and lowers pulmonary arterial pressure (PAP). Endothelial, but not smooth muscle, knockout of Panx1 increased PA contractility and raised PAP in mice. Flow/shear stress increased ATP efflux through endothelial Panx1 in PAs. Panx1-effluxed extracellular ATP signaled through purinergic P2Y2 receptor (P2Y2R) to activate protein kinase Cα (PKCα), which in turn activated endothelial TRPV4 channels. Finally, caveolin-1 provided a signaling scaffold for endothelial Panx1, P2Y2R, PKCα, and TRPV4 channels in PAs, promoting their spatial proximity and enabling signaling interactions. These results indicate that endothelial Panx1–P2Y2R–TRPV4 channel signaling, facilitated by caveolin-1, reduces PA contractility and lowers PAP in mice.