期刊
DEVELOPMENTAL CELL
卷 57, 期 10, 页码 1211-+出版社
CELL PRESS
DOI: 10.1016/j.devcel.2022.03.019
关键词
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资金
- Cancer Research UK [A20145]
- Wellcome Trust [088785/Z/09/Z]
- Swiss National Science Foundation
- Wellcome Trust [088785/Z/09/Z] Funding Source: Wellcome Trust
This study reveals that mitochondrial dysfunction can promote cancer through the regulation of mitochondrial dynamics and caspase-dependent DNA damage, deepening our understanding of the association between mitochondria and cancer.
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.
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