Autophagic cell death is dependent on lysosomal membrane permeability through bax and bak
Open accessAbstract
Cells deficient in the pro-death Bcl-2 family members Bax and Bak are known to be resistant to apoptotic cell death, and previous we have shown that these two effectors are also needed for mitochondrial-dependent cellular necrosis (Karch et al., 2013). 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.
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This led to the identification of some of the earliest disease-associated genes, including APP, PS1 and PS2 in AD, SNCA and LRRK2 in PD and MAPT and GRN in FTD.
“This subsequently led to the identification of some of the earliest disease-associated genes, including APP, PS1 and PS2 in AD, SNCA and LRRK2 in PD and MAPT and GRN in FTD.79–87”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [83]
The Results and Materials and methods passages concern Bax/Bak-mediated cell death, not the identification of genes associated with AD, PD, or FTD. Searches for APP, PS1, PS2, SNCA, LRRK2, MAPT, and GRN, and for the three diseases, found no passage addressing the claim. (LLM, conf=0.78)
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- Authors
- Karch, J., Schips, T. G., Maliken, B. D., Brody, M. J., Sargent, M. A., Kanisicak, O., & Molkentin, J. D.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Molkentin, Jeffery D
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2017-11-17
- Volume
- 6
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5697932
- OpenAlex
- W2768129277
- Cited by
- 91
- References
- 3
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 5 · 2023: 6 · 2022: 17 · 2021: 14 · 2020: 15 · 2019: 7 · 2018: 13
- FWCI
- 7.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Howard Hughes Medical Institute (Molkentin)
- National Institutes of Health (R01HL132831)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- autophagic cell death, lysosomal membrane permeability, Bax, Bak, Bcl-2 family proteins, lysosomes, mouse embryonic fibroblasts, cell death regulation
- MeSH terms
- Animals, Autophagy, Cell Membrane, Cells, Cultured, Fibroblasts, Lysosomes, Permeability, Gene Deletion, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Mice
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