Mitochondrial DNA in cell death and inflammation

Heilig, R., Lee, J. and Tait, S. W.G. (2023) Mitochondrial DNA in cell death and inflammation. Biochemical Society Transactions, 51(1), pp. 457-472. (doi: 10.1042/BST20221525) (PMID:36815695) (PMCID:PMC9988000)

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Cytosolic DNA is recognized by the innate immune system as a potential threat. During apoptotic cell death, mitochondrial DNA (mtDNA) release activates the DNA sensor cyclic GMP–AMP synthase (cGAS) to promote a pro-inflammatory type I interferon response. Inflammation following mtDNA release during apoptotic cell death can be exploited to engage anti-tumor immunity and represents a potential avenue for cancer therapy. Additionally, various studies have described leakage of mtDNA, independent of cell death, with different underlying cues such as pathogenic infections, changes in mtDNA packaging, mtDNA stress or reduced mitochondrial clearance. The interferon response in these scenarios can be beneficial but also potentially disadvantageous, as suggested by a variety of disease phenotypes. In this review, we discuss mechanisms underlying mtDNA release governed by cell death pathways and summarize release mechanisms independent of cell death. We further highlight the similarities and differences in mtDNA release pathways, outlining gaps in our knowledge and questions for further research. Together, a deeper understanding of how and when mtDNA is released may enable the development of drugs to specifically target or inhibit mtDNA release in different disease settings.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Tait, Professor Stephen and Heilig, Dr Rosalie
Authors: Heilig, R., Lee, J., and Tait, S. W.G.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Biochemical Society Transactions
Publisher:Portland Press
ISSN (Online):1470-8752
Published Online:23 February 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Biochemical Society Transactions 51(1): 457-472
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172007Apoptosis as an oncogenic process: understanding and exploiting its dark-sideStephen TaitCancer Research UK (CRUK)C40872/A20145Institute of Cancer Sciences