生物
线粒体DNA
线粒体融合
DNA损伤
线粒体
细胞生物学
线粒体分裂
DNAJA3公司
DNA
遗传学
基因
作者
Kai Cao,Joel S. Riley,Rosalie Heilig,Alfredo E. Montes-Gómez,Esmee Vringer,Kévin Berthenet,Catherine Cloix,Yassmin Elmasry,David G. Spiller,Gabriel Ichim,Kirsteen J. Campbell,Andrew Gilmore,Stephen W. G. Tait
标识
DOI:10.1016/j.devcel.2022.03.019
摘要
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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