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Mechanisms of BCL-2 family proteins in mitochondrial apoptosis

Nature Reviews Molecular Cell Biology volume 24, pages 732–748 (2023)Cite this article

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Abstract

The proteins of the BCL-2 family are key regulators of mitochondrial apoptosis, acting as either promoters or inhibitors of cell death. The functional interplay and balance between the opposing BCL-2 family members control permeabilization of the outer mitochondrial membrane, leading to the release of activators of the caspase cascade into the cytosol and ultimately resulting in cell death. Despite considerable research, our knowledge about the mechanisms of the BCL-2 family of proteins remains insufficient, which complicates cell fate predictions and does not allow us to fully exploit these proteins as targets for drug discovery. Detailed understanding of the formation and molecular architecture of the apoptotic pore in the outer mitochondrial membrane remains a holy grail in the field, but new studies allow us to begin constructing a structural model of its arrangement. Recent literature has also revealed unexpected activities for several BCL-2 family members that challenge established concepts of how they regulate mitochondrial permeabilization. In this Review, we revisit the most important advances in the field and integrate them into a new structure–function-based classification of the BCL-2 family members that intends to provide a comprehensive model for BCL-2 action in apoptosis. We close this Review by discussing the potential of drugging the BCL-2 family in diseases characterized by aberrant apoptosis.

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Fig. 1: The BCL-2 family.
Fig. 2: The BCL-2 fold.
Fig. 3: Activation and oligomerization of executioner proteins.

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Acknowledgements

Research in the P.E.C.’s laboratory is supported by an NHMRC Ideas Grant (GNT2001406) and Investigator Fellowship (GNT2009062), the Leukaemia and Lymphoma Society (SCOR 7015-1), Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC IRIISS. A.J.G.-S. acknowledges funding by the European Research Council (grant agreement 817758) and the Deutsche Forschungsgemeinschaft (CRC1403 Projektnummer 414786233 and CRC1218 Projektnummer 269925409).

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  1. These authors contributed equally: Peter E. Czabotar, Ana J. Garcia-Saez.

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  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

    Peter E. Czabotar

  2. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia

    Peter E. Czabotar

  3. Membrane Biophysics, Institute of Genetics, CECAD, University of Cologne, Cologne, Germany

    Ana J. Garcia-Saez

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P.E.C. is an employee of the Walter and Eliza Hall Institute, which has an agreement with Genentech and AbbVie, and receives milestone and royalty payments related to Venetoclax. Employees of Walter and Eliza Hall Institute may be eligible for financial benefits related to these payments. P.E.C. receives such a financial benefit as a result of previous research related to Venetoclax. P.E.C. has received research funding from Genentech. A.J.G.-S. declares no competing interests.

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Czabotar, P.E., Garcia-Saez, A.J. Mechanisms of BCL-2 family proteins in mitochondrial apoptosis. Nat Rev Mol Cell Biol 24, 732–748 (2023). https://doi.org/10.1038/s41580-023-00629-4

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