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)

Abstract

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
• Status: Published
• Refereed: Yes
• 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: 0300-5127
• 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
172007		Apoptosis as an oncogenic process: understanding and exploiting its dark-side	Stephen Tait	Cancer Research UK (CRUK)	C40872/A20145	Institute of Cancer Sciences