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)

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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:Campbell, Dr Kirsteen and Elmasry, Ms Yassmin and Tait, Professor Stephen and Ichim, Dr Gabriel and Cloix, Dr Catherine and Heilig, Dr Rosalie and Riley, Dr Joel and Vringer, Esmee and Montes Gomez, Mr Alfredo and Cao, Dr Kai
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

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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