Autophagic cell death is dependent on lysosomal membrane permeability through Bax and Bak
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
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
- Fiona M Watt, King's College London, United Kingdom
Version history
- Received: July 19, 2017
- Accepted: November 16, 2017
- Accepted Manuscript published: November 17, 2017 (version 1)
- Version of Record published: November 21, 2017 (version 2)
- 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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