Cited by 26Cell death mechanisms and regulationMitochondrial Function and PathologyAutophagy in Disease and Therapy

Apoptotic priming is defined by the dynamic exchange of Bcl-2 proteins between mitochondria and cytosol

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King, Louise E., Rodriguez-Enriquez, Ricardo, Pedley, Robert, Mellor, Charlotte E. L., Wang, Pengbo, Zindy, Egor, White, Michael R. H., Brennan, Keith +1 more·2022·Cell Death & Differentiation

Abstract

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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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.
Venue
Cell Death & Differentiation
Published
2022-05-18
Volume
29
Issue
11
Pages
2262-2274
ISSN
  • 1350-9047 (ISSN-L)
  • 1476-5403
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
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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