Apoptotic priming is defined by the dynamic exchange of Bcl-2 proteins between mitochondria and cytosol
Open accessAbstract
Apoptosis is regulated by interactions between the BH3-only and multi-domain Bcl-2 family proteins. These interactions are integrated on the outer mitochondrial membrane (OMM) where they set the threshold for apoptosis, known as mitochondrial priming. However, how mitochondrial priming is controlled at the level of single cells remains unclear. Retrotranslocation of Bcl-XL has been proposed as one mechanism, removing pro-apoptotic Bcl-2 proteins from the OMM, thus reducing priming. Contrary to this view, we now show that Bcl-XL retrotranslocation is inhibited by binding to its BH3-only partners, resulting in accumulation of these protein complexes on mitochondria. We find that Bcl-XL retrotranslocation dynamics are tightly coupled to mitochondrial priming. Quantifying these dynamics indicates the heterogeneity in priming between cells within a population and predicts how they subsequently respond to a pro-apoptotic signal.
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Bcl-2 proteins are considered a particularly challenging class of undruggable targets.
“Consequently, Bcl-2 proteins are considered a particularly challenging class of undruggable targets.490,491”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [490]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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- Authors
- King, L. E., Rodriguez-Enriquez, R., Pedley, R., Mellor, C. E. L., Wang, P., Zindy, E., White, M. R. H., Brennan, K., & Gilmore, A. P.
- Affiliations
- University of Cologne (DE)
- St. Jude Children's Research Hospital (US)
- Wellcome Centre for Cell-Matrix Research (GB)
- Université Libre de Bruxelles (BE)
- Manchester Academic Health Science Centre (GB)
- University of Manchester (GB)
- Corresponding author
- Gilmore, Andrew P.
- ORCID
- Venue
- Cell Death & Differentiation
- Published
- 2022-05-18
- Volume
- 29
- Issue
- 11
- Pages
- 2262-2274
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC9613888
- OpenAlex
- W4280608246
- Cited by
- 26
- References
- 45
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 7 · 2023: 8
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cell Death and Differentiation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, cc-by)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
- Funders
- Cancer Research UK
- Wellcome Trust (204796/Z/16/Z, 088785/Z/09/Z)
- Breast Cancer Now
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- apoptosis, mitochondrial priming, Bcl-2 family proteins, BH3-only proteins, mitochondrial outer membrane, mitochondrial membrane potential, single-cell heterogeneity, pro-apoptotic signaling
- MeSH terms
- Cytosol, Mitochondria, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Apoptosis Regulatory Proteins, bcl-X Protein, bcl-2-Associated X Protein, Mitochondrial Membranes
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