Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage

Cao, K. et al. (2022) Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage. Developmental Cell, 57(10), 1211-1225.e6. (doi: 10.1016/j.devcel.2022.03.019) (PMID:35447090) (PMCID:PMC9616799)

Abstract

Mitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer is poorly understood. We find that mitochondrial dysfunction promotes DNA damage under conditions of increased apoptotic priming. Underlying this process, we reveal a key role for mitochondrial dynamics in the regulation of DNA damage and genome instability. The ability of mitochondrial dynamics to regulate oncogenic DNA damage centers upon the control of minority mitochondrial outer membrane permeabilization (MOMP), a process that enables non-lethal caspase activation leading to DNA damage. Mitochondrial fusion suppresses minority MOMP and its associated DNA damage by enabling homogeneous mitochondrial expression of anti-apoptotic BCL-2 proteins. Finally, we find that mitochondrial dysfunction inhibits pro-apoptotic BAX retrotranslocation, causing BAX mitochondrial localization and thereby promoting minority MOMP. Unexpectedly, these data reveal oncogenic effects of mitochondrial dysfunction that are mediated via mitochondrial dynamics and caspase-dependent DNA damage.

• Item Type: Articles
• Additional Information: This research was supported by funding from the Cancer Research UK (A20145; S.W.G.T.). The Wellcome Centre for Cell-Matrix Research is supported by Wellcome Trust (088785/Z/09/Z). R.H. is supported by a fellowship from the Swiss National Science Foundation.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Heilig, Dr Rosalie and Campbell, Dr Kirsteen and Elmasry, Ms Yassmin and Riley, Dr Joel and Tait, Professor Stephen and Vringer, Esmee and Cloix, Dr Catherine and Ichim, Dr Gabriel and Cao, Dr Kai and Montes Gomez, Mr Alfredo
• Authors: Cao, K., Riley, J. S., Heilig, R., Montes-Gómez, A. E., Vringer, E., Berthenet, K., Cloix, C., Elmasry, Y., Spiller, D. G., Ichim, G., Campbell, K. J., Gilmore, A. P., and Tait, S. W.G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Developmental Cell
• Publisher: Elsevier (Cell Press)
• ISSN: 1534-5807
• ISSN (Online): 1878-1551
• Published Online: 20 April 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Developmental Cell 57(10): 1211-1225.e6
• 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