1. Developmental Biology
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Autophagic cell death is dependent on lysosomal membrane permeability through Bax and Bak

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Cite this article as: eLife 2017;6:e30543 doi: 10.7554/eLife.30543

Abstract

Cells deficient in the pro-death Bcl-2 family members Bax and Bak are known to be resistant to apoptotic cell death, and in a previous eLIFE paper, Karch et al., 2013 showed that these 2 effectors are also needed for mitochondrial-dependent cellular necrosis. Here we show that mouse embryonic fibroblasts deficient in Bax/Bak1 are resistant to the third major form of cell death associated with autophagy through a mechanism involving lysosome permeability. Indeed, specifically targeting Bax only to the lysosome restores autophagic cell death in Bax/Bak1 null cells. Moreover, a monomeric-only mutant form of Bax is sufficient to increase lysosomal membrane permeability and restore autophagic cell death in Bax/Bak1 double-deleted mouse embryonic fibroblasts. Finally, increasing lysosomal permeability through a lysomotropic detergent in cells devoid of Bax/Bak1 restores autophagic cell death, collectively indicting that Bax/Bak integrate all major forms of cell death through direct effects on membrane permeability of multiple intracellular organelles.

Article and author information

Author details

  1. Jason Karch

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Tobias G Schips

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Bryan D Maliken

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Matthew J Brody

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Michelle A Sargent

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Onur Kanisciak

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jeffery D Molkentin

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, United States
    For correspondence
    jeff.Molkentin@cchmc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3558-6529

Funding

National Institutes of Health (R01HL132831)

  • Jeffery D Molkentin

Howard Hughes Medical Institute (Molkentin)

  • Jeffery D Molkentin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Fiona M Watt, King's College London, United Kingdom

Publication history

  1. Received: July 19, 2017
  2. Accepted: November 16, 2017
  3. Accepted Manuscript published: November 17, 2017 (version 1)
  4. Version of Record published: November 21, 2017 (version 2)
  5. Version of Record updated: December 13, 2017 (version 3)

Copyright

© 2017, Karch 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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