Abstract
Mitochondria are cellular factories for energy production, calcium homeostasis and iron metabolism, but they also have an unequivocal and central role in intrinsic apoptosis through the release of cytochrome c. While the subsequent activation of proteolytic caspases ensures that cell death proceeds in the absence of collateral inflammation, other phlogistic cell death pathways have been implicated in using, or engaging, mitochondria. Here we discuss the emerging complexities of intrinsic apoptosis controlled by the BCL-2 family of proteins. We highlight the emerging theory that non-lethal mitochondrial apoptotic signalling has diverse biological roles that impact cancer, innate immunity and ageing. Finally, we delineate the role of mitochondria in other forms of cell death, such as pyroptosis, ferroptosis and necroptosis, and discuss mitochondria as central hubs for the intersection and coordination of cell death signalling pathways, underscoring their potential for therapeutic manipulation.
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Acknowledgements
We apologize to the authors whose work we were unable to cite and discuss due to word and reference limits. H.L.G. and S.W.G.T. are supported by funding from Cancer Research UK (DRCNPG-Jun22\100011). A.S. is supported by a scholarship from the University of Melbourne (MIRS and MIFRS). G.D. is supported through a fellowship from the Bodhi Education Fund. We thank S. Masaldan, A. Samson, T. Saunders and J. Vince for discussions, comments and suggestions.
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Glover, H.L., Schreiner, A., Dewson, G. et al. Mitochondria and cell death. Nat Cell Biol (2024). https://doi.org/10.1038/s41556-024-01429-4
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DOI: https://doi.org/10.1038/s41556-024-01429-4
